NeuroImage

Published by Elsevier
Online ISSN: 1095-9572
Publications
Article
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.
 
Direct observation of the 0.1 Hz hemodynamic oscillations in the awake human brain (A) Grayscale image of subject 1 craniotomy under 530 nm illumination with 4 regions of interest (ROIs) indicated. (B) 4 corresponding time courses showing ΔHbT, ΔHbO and ΔHbR dynamics for each ROI indicated in A. (C) Power spectrum (abs(FFT)) of ΔHbT time courses shown in B. Green arrow indicates SSHO at ∼0.1 Hz. (D) Log-log abs(FFT) plot over wider frequency range showing otherwise 1/f shape. Heart-rate (2 Hz) is indicated by the thick blue arrow, breathing (0.4 Hz) with a thin blue arrow and the SSHO with a green arrow. (E) Fourier image of the field of view at 0.1 Hz, delineating 3 distinct vascular networks, outlined with white dashed ovals (stars indicate artifacts from specular reflections). (F) Fourier image at 0.15 Hz, away from the 0.1 Hz peak in the power spectrum, showing no delineated regions.
Non-sinusoidal low frequency hemodynamics in a second human subject (A) Grayscale image of subject 2 craniotomy under 530 nm illumination with 4 ROIs indicated. (B) 4 corresponding time courses showing ΔHbT, ΔHbO and ΔHbR dynamics for each ROI indicated in A. (C) Power spectrum (abs(FFT)) of HbT time courses shown in B with 0.17 Hz breathing rate indicated by thin blue arrow. (D) Log-log abs(FFT) plot of wider frequency range with thicker blue arrows indicating heart rate (1 Hz) and its harmonic (2 Hz). (E) Fourier image of the field of view at 0.1 Hz, and (F) a Fourier image at 0.15 Hz. Stars indicate artifacts from specular reflections. No distinct vascular networks are apparent in either image. A movie of ΔHbT dynamics in subject 2 is shown in supplemental movie M2.
Properties of the ∼0.1 Hz oscillation in the human brain (A) Pearson correlation coefficient image using the ΔHbT time course from ROI 3 in Figure 1. (B,C) Magnification and corresponding comparison of the correlation image with raw green channel grayscale image of the region indicated by the white dashed box in A. Note the large vascular network delineated by the correlation image extends under the large vein (black arrow). (D) Change in vessel diameter relating to change in ΔHbT over vessel indicated by white arrow in C. Light brown indicates raw vessel diameter time course, dark brown is the raw vessel diameter time course low pass filtered at 0.2 Hz. (E) Wave-like propagation of the 0.1 Hz oscillation depicted ασ a ΔHbT kymograph image of time courses extracted along the long dashed yellow ROI in A and in yellow in the inset gray scale image below (F). Red arrows mark pixels corresponding to blood vessels. Black arrow indicates the direction of a single wave's propagation. Equivalent data from two more trials is shown in supplementary figures S1 and S2. White arrow indicates a point of merge. (G) Using cross-correlation analysis, time lags between ∼0.1 Hz oscillating time courses extracted from 4 ROIs shown on the grayscale image to the left demonstrate directional propagation of the SSHO wave.
Observation of 0.1 Hz oscillation in pre-operative fMRI BOLD signal in subject 1 (A) Optical field of view and (B) correspondingly oriented field of view on the MRI outlined by a white dashed region showing 2 ROIs. (C) Additional deeper horizontal section showing an ROI over the left hand region in the right motor cortex. Sagittal view showing the location of the horizontal sections is displayed on the top right for B and C. A = anterior, P = posterior, R = right. (D) BOLD signal responses to left hand task in ROI 1. (E,F) BOLD signal time course from ROI 2 and ROI 3. Black crosses mark measured BOLD time-points. A spline interpolated trace is also shown in each case. (G) Power spectra (abs(FFT)) showing a ∼0.1 Hz peak in ROI 2 (indicated by the green arrow). Peak frequency corresponding to the left hand task is indicated by the brown arrow. (inset) Power spectra (abs(FFT)) from (G) plotted on a log-log scale, showing 1/f behavior. (H,I,J) Saggital, coronal and horizontal views of subject 1 respectively, showing the location and extent of the tumor.
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
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.
 
Article
Neuropathic pain can be both ongoing or stimulus-induced. Stimulus-induced pain, also known as hyperalgesia, can be differentiated into primary and secondary hyperalgesia. The former results from sensitization of peripheral nociceptive structures, the latter involves sensitization processes within the central nervous system (CNS). Hypersensitivity towards heat stimuli, i.e. thermal hyperalgesia, is a key feature of primary hyperalgesia, whereas secondary hyperalgesia is characterized by hypersensitivity towards mechanical (e.g. pin-prick) stimulation. Using functional magnetic resonance imaging (fMRI), we investigated if brain activation patterns associated with primary and secondary hyperalgesia might differ. Thermal and pin-prick hyperalgesia were induced on the left forearm in 12 healthy subjects by topical capsaicin (2.5%, 30 min) application. Equal pain intensities of both hyperalgesia types were applied during fMRI experiments, based on previous quantitative sensory testing. Simultaneously, subjects had to rate the unpleasantness of stimulus-related pain. Pin-prick hyperalgesia (i.e. subtraction of brain activations during pin-prick stimulation before and after capsaicin exposure) led to activations of primary and secondary somatosensory cortices (S1 and S2), associative-somatosensory cortices, insula and superior and inferior frontal cortices (SFC, IFC). Brain areas activated during thermal hyperalgesia (i.e. subtraction of brain activations during thermal stimulation before and after capsaicin exposure) were S1 and S2, insula, associative-somatosensory cortices, cingulate cortex (GC), SFC, middle frontal cortex (MFC) and IFC. When compared to pin-prick hyperalgesia, thermal hyperalgesia led to an increased activation of bilateral anterior insular cortices, MFC, GC (Brodmann area 24' and 32') and contralateral SFC and IFC, despite equal pain intensities. Interestingly, stronger activations of GC, contralateral MFC and anterior insula significantly correlated to higher ratings of the stimulus-related unpleasantness. We conclude that thermal and mechanical hyperalgesia produce substantially different brain activation patterns. This is linked to different psychophysical properties.
 
Article
11C-labeled neuroreceptor ligands frequently require long scan durations to quantify ligand-receptor binding. In this paper, we compare the accuracy of two three-dimensional (3D) positron emission tomography (PET) reconstructions: ordered-subset expectation-maximization (OS-EM) versus filtered backprojection (FBP) under low count rate conditions exhibited by 11C neuroreceptor studies. Data were obtained from a dynamic 11C phantom acquisition as well as six dynamic human [11C] WAY-100635 studies, all acquired in 3D mode using the EXACT HR+ PET scanner. Model-based scatter correction of the phantom datum was found to overcorrect in low count rate situations producing a negative bias in FBP reconstruction and a positive bias in OS-EM reconstruction, the OS-EM bias attributed to the non-negativity constraint of sinogram values. In the phantom OS-EM and FBP, reconstruction bias occurred at activities less than 25 Bq/cm3. In the human cerebellum, OS-EM deviated from FBP at activities less than 50 Bq/cm3. The total volume of distribution (VT), as determined from the metabolite corrected arterial input function and a two-tissue compartment kinetic model, was more sensitive to the positive bias of OS-EM than the negative bias of FBP at low count rates. To avoid reconstruction bias with 3D PET studies using the HR+, the scan duration should be limited so as to yield a final non-decay-corrected activity concentration of no less than 50 Bq/cm3. In neuroreceptor studies, if such a low count rate cannot be avoided, FBP reconstruction is preferable to OS-EM to estimate VT.
 
Article
Unlabelled: image- derived input functions (IDIFs) represent a promising technique for a simpler and less invasive quantification of PET studies as compared to arterial cannulation. However, a number of limitations complicate the routine use of IDIFs in clinical research protocols and the full substitution of manual arterial samples by venous ones has hardly been evaluated. This study aims for a direct validation of IDIFs and venous data for the quantification of serotonin-1A receptor binding (5-HT(1A)) with [carbonyl-(11)C]WAY-100635 before and after hormone treatment. Methods: Fifteen PET measurements with arterial and venous blood sampling were obtained from 10 healthy women, 8 scans before and 7 after eight weeks of hormone replacement therapy. Image-derived input functions were derived automatically from cerebral blood vessels, corrected for partial volume effects and combined with venous manual samples from 10 min onward (IDIF+VIF). Corrections for plasma/whole-blood ratio and metabolites were done separately with arterial and venous samples. 5-HT(1A) receptor quantification was achieved with arterial input functions (AIF) and IDIF+VIF using a two-tissue compartment model. Results: Comparison between arterial and venous manual blood samples yielded excellent reproducibility. Variability (VAR) was less than 10% for whole-blood activity (p>0.4) and below 2% for plasma to whole-blood ratios (p>0.4). Variability was slightly higher for parent fractions (VARmax=24% at 5 min, p<0.05 and VAR<13% after 20 min, p>0.1) but still within previously reported values. IDIFs after partial volume correction had peak values comparable to AIFs (mean difference Δ=-7.6 ± 16.9 kBq/ml, p>0.1), whereas AIFs exhibited a delay (Δ=4 ± 6.4s, p<0.05) and higher peak width (Δ=15.9 ± 5.2s, p<0.001). Linear regression analysis showed strong agreement for 5-HT(1A) binding as obtained with AIF and IDIF+VIF at baseline (R(2)=0.95), after treatment (R(2)=0.93) and when pooling all scans (R(2)=0.93), with slopes and intercepts in the range of 0.97 to 1.07 and -0.05 to 0.16, respectively. In addition to the region of interest analysis, the approach yielded virtually identical results for voxel-wise quantification as compared to the AIF. Conclusions: Despite the fast metabolism of the radioligand, manual arterial blood samples can be substituted by venous ones for parent fractions and plasma to whole-blood ratios. Moreover, the combination of image-derived and venous input functions provides a reliable quantification of 5-HT(1A) receptors. This holds true for 5-HT(1A) binding estimates before and after treatment for both regions of interest-based and voxel-wise modeling. Taken together, the approach provides less invasive receptor quantification by full independence of arterial cannulation. This offers great potential for the routine use in clinical research protocols and encourages further investigation for other radioligands with different kinetic characteristics.
 
Article
PET studies of [(11)C]WAY-100635 binding are proving to be a useful tool to evaluate 5-HT(1A) receptor function in vivo in humans. We describe the pattern of [(11)C]WAY-100635 binding in 61 healthy male brains and examine its variability. For all PET scans, binding potential (BP) values for [(11)C]WAY-100635 in different regions were calculated using a simplified reference tissue model, with the cerebellum as reference region. Specifically we describe (1) region of interest and SPM databases of PET [(11)C]WAY-100635 binding, including test-retest variability; (2) the sensitivity of [(11)C]WAY-100635 binding to manipulations of endogenous 5-HT; and (3) correlations between [(11)C]WAY-100635 binding and radiochemical, demographic, physiological, and behavioral variables. The regional distribution of [(11)C]WAY-100635 binding in healthy human brain was similar to that reported in vitro. The test-retest variability was approximately 12% (range 9-16%) and was similar for all methods of regional sampling. The binding of [(11)C]WAY-100635 was insensitive to changes in brain 5-HT induced by tryptophan infusion and depletion. Although BP values varied greatly across subjects (range 2.9-6.8), there were no significant correlations of regional and global BP with common radiochemical, demographic, physiological, and personality variables. Specifically, in contrast with two recent small studies, we found no decline of [(11)C]WAY-100635 binding with age in our large cohort over the age range of 24 to 53 years. Assessment of 5-HT(1A) receptors in vivo using PET and [(11)C]WAY-100635 gives reliable measures of 5-HT(1A) binding. The large between-subject variability observed could not be explained by common methodological, physiological, or behavioral factors and hence the biological basis of this variability remains to be clarified.
 
Article
In positron emission tomography (PET) studies, the detailed mapping of neuroreceptor binding is a trade-off between parametric accuracy and spatial precision. Logan's graphical approach is a straightforward way to quickly obtain binding potential values at the voxel level but it has been shown to have a noise-dependent negative bias. More recently suggested approaches claim to improve parametric accuracy with retained spatial resolution. In the present study, we used PET measurements on regional D2 dopamine and 5-HT1A serotonin receptor binding in man to compare binding potential (BP) estimates of six different parametric imaging approaches to the traditional Logan ROI-based approach which was used as a "gold standard". The parametric imaging approaches included Logan's reference tissue graphical analysis (PILogan), its version recently modified by Varga and Szabo (PIVarga), two versions of the wavelet-based approach, Gunn's basis function method (BFM) and Gunn et al.'s recent compartmental theory-based approach employing basis pursuit strategy for kinetic modeling (called DEPICT). Applicability for practical purposes in basic and clinical research was also considered. The results indicate that the PILogan and PIVarga approaches fail to recover the correct values, the wavelet-based approaches overcome the noise susceptibility of the Logan fit with generally good recovery of BP values, and BFM and DEPICT seem to produce values with a bias dependent on receptor density. Further investigations on this bias and other phenomena revealed fundamental issues regarding the use of BFM and DEPICT on noisy voxel-wise data. In conclusion, the wavelet-based approaches seem to provide the most valid and reliable estimates across regions with a wide range of receptor densities. Furthermore, the results support the use of receptor parametric imaging in applied studies in basic or clinical research.
 
Article
[Carbonyl-11C]WAY-100635 is a promising PET radioligand for the 5-HT1A receptor, having demonstrated more favorable characteristics for in vivo imaging than the previously available [O-methyl-11C]WAY-100635. The current study evaluates different tracer kinetic modelling strategies for the quantification of 5-HT1A receptor binding in human brain. Mathematical modelling of the carbonyl-labeled radiotracer is investigated using compartmental structures, including both plasma input and reference tissue approaches. Furthermore, the application of basis function methods allows for the investigation of parametric imaging, providing functional maps of both delivery and binding of the radioligand. Parameter estimates of binding from normal volunteers indicate a low intra- versus a high intersubject variability. It is concluded that a simplified reference tissue approach may be used to quantify 5-HT1A binding either in terms of ROI data or as parametric images.
 
Article
A component based method (CompCor) for the reduction of noise in both blood oxygenation level-dependent (BOLD) and perfusion-based functional magnetic resonance imaging (fMRI) data is presented. In the proposed method, significant principal components are derived from noise regions-of-interest (ROI) in which the time series data are unlikely to be modulated by neural activity. These components are then included as nuisance parameters within general linear models for BOLD and perfusion-based fMRI time series data. Two approaches for the determination of the noise ROI are considered. The first method uses high-resolution anatomical data to define a region of interest composed primarily of white matter and cerebrospinal fluid, while the second method defines a region based upon the temporal standard deviation of the time series data. With the application of CompCor, the temporal standard deviation of resting-state perfusion and BOLD data in gray matter regions was significantly reduced as compared to either no correction or the application of a previously described retrospective image based correction scheme (RETROICOR). For both functional perfusion and BOLD data, the application of CompCor significantly increased the number of activated voxels as compared to no correction. In addition, for functional BOLD data, there were significantly more activated voxels detected with CompCor as compared to RETROICOR. In comparison to RETROICOR, CompCor has the advantage of not requiring external monitoring of physiological fluctuations.
 
Article
We present a method for investigating the dynamic pharmacological modulation of pain-related brain activity, measured by BOLD-contrast fMRI. Noxious thermal stimulation was combined with a single infusion and washout of remifentanil, a short-acting opioid analgesic agent. The temporal profile of the effect site concentration of remifentanil, estimated from a pharmacokinetic model, was incorporated into a linear model of the fMRI data. The methodology was tested in nine healthy male subjects. During each imaging session the subjects received noxious thermal stimulation to the back of the left hand, prior to infusion, during infusion to a remifentanil effect site concentration of 1.0 ng/ml, and during washout of the remifentanil. Infusions were repeated with saline. Remifentanil-induced analgesia was confirmed from subjective pain intensity scores. Pain-related brain activity was identified in a matrix of regions using a linear model of the transient BOLD responses to noxious stimulation. Of those regions, there was a significant fractional reduction in the amplitude of the pain-related BOLD response in the insular cortex contralateral to the stimulus, the ipsilateral insular cortex, and the anterior cingulate cortex. Statistical parametric mapping of the component of pain-related BOLD responses that was linearly scaled by remifentanil concentration confirmed the contralateral insular cortex as the pain-processing region most significantly modulated by remifentanil compared to saline. The mapping of specific modulation of pain-related brain activity is directly relevant for understanding pharmacological analgesia. The method of examining time-dependent pharmacological modulation of specific brain activity may be generalized to other drugs that modulate brain activity other than that associated with pain.
 
Article
Decision making involves the allocation of cognitive resources in response to expectations and feedback. Here we explored how frontal networks respond in a gambling paradigm in which uncertainty was manipulated to increase demands for cognitive control. In one experiment, pupil diameter covaried with uncertainty during decision making and with the degree to which subsequent outcomes violated reward expectations. In a second experiment, fMRI showed that both uncertainty and unexpected outcomes modulated activation in a network of frontal regions. Thus, the frontal network supports multiple phases of the decision-making process including information regarding reward uncertainty and reward outcome. In contrast, striatal activation only tracked reward delivery, suggesting a distinct reward pathway that might, under certain circumstances, oppose the frontal network. These results are consistent with the interpretation that reward signals may bias recruitment of frontal networks that are linked to allocation of cognitive resources.
 
Article
Correlation and causality metrics can be applied to blood-oxygen level-dependent (BOLD) signal time series in order to infer neural synchrony and directions of information flow from fMRI data. However, the BOLD signal reflects both the underlying neural activity and the vascular response, the latter of which is governed by local vasomotor physiology. The presence of potential vascular latency differences thus poses a confound in the detection of neural synchrony as well as inferences about the causality of neural processes. In the present study, we investigate the use of a breath holding (BH) task for characterizing and correcting for voxel-wise neurovascular latency differences across the whole brain. We demonstrate that BH yields reliable measurements of relative timing differences between voxels, and further show that a BH-derived latency correction can impact both functional connectivity maps of the resting-state default-mode network and activation maps of an event-related working memory (WM) task.
 
Article
This study aimed to determine regional pattern of tissue perfusion in the normal-appearing white matter (NAWM) of patients with primary-progressive (PP), relapsing-remitting (RR) multiple sclerosis (MS) and healthy controls, and to investigate the association between perfusion abnormalities and clinical disability. Using dynamic susceptibility contrast (DSC) perfusion MRI at 3 T, we studied 22 patients with clinically definite MS, 11 with PP-MS and 11 with RR-MS and 11 age- and gender-matched healthy volunteers. The MRI protocol included axial dual-echo, dynamic susceptibility contrast enhanced (DSC) T2*-weighted and post-contrast T1-weighted images. Absolute cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the periventricular, frontal, occipital NAWM and in the splenium of the corpus callosum. Compared to controls, CBF and CBV were significantly lower in all NAWM regions in both PP-MS patients (p values from <0.0001 to 0.001) and RR-MS (p values from <0.0001 to 0.020). Compared to RR-MS, PP-MS patients showed significantly lower CBF in the periventricular NAWM (p=0.002) and lower CBV in the periventricular and frontal NAWM (p values: 0.0029 and 0.022). EDSS was significantly correlated with the periventricular CBF (r=-0.48, p=0.0016) and with the periventricular and frontal CBV (r=-0.42, p=0.015; r=-0.35, p=0.038, respectively). This study suggests that the hemodynamic abnormalities of NAWM have clinical relevance in patients with MS. DSC perfusion MRI might provide a relevant objective measure of disease activity and treatment efficacy.
 
Article
Growing evidence suggests that interval timing in humans is supported by distributed brain networks. Recently, we demonstrated that the specific network recruited for the performance of rhythmic timing is not static but is influenced by the coordination pattern employed during interval acquisition. Here we expand on this previous work to investigate the role of stimulus modality and coordination pattern in determining the brain areas recruited for performance of a self-paced rhythmic timing task. Subjects were paced with either a visual or an auditory metronome in either a synchronized (on the beat) or syncopated (off the beat) coordination pattern. The pacing stimulus was then removed and subjects continued to move based on the required interval. When compared with networks recruited for auditory pacing and continuation, the visual-specific activity was observed in the classic dorsal visual stream that included bilateral MT/V5, bilateral superior parietal lobe, and right ventral premotor cortex. Activity in these regions was present not only during pacing, when visual information is used to guide motor behavior, but also during continuation, when visual information specifying the temporal interval was no longer present. These results suggest a role for modality-specific areas in processing and representing temporal information. The cognitive demands imposed by syncopated coordination resulted in increased activity in a broad network that included supplementary motor area, lateral pre-motor cortex, bilateral insula, and cerebellum. This coordination-dependent activity persisted during the subsequent continuation period, when stimuli were removed and no coordination constraints were imposed. Taken together, the present results provide additional evidence that time and timing are served by a context-dependent distributed network rooted in basic sensorimotor processes.
 
Article
We investigated the relation between cognitive processing speed and structural properties of white matter pathways via convergent imaging studies in healthy and brain-injured groups. Voxel-based morphometry (VBM) was applied to diffusion tensor imaging data from thirty-nine young healthy subjects in order to investigate the relation between processing speed, as assessed with the Digit-Symbol subtest from WAIS-III, and fractional anisotropy, an index of microstructural organization of white matter. Digit-Symbol performance was positively correlated with fractional anisotropy of white matter in the parietal and temporal lobes bilaterally and in the left middle frontal gyrus. Fiber tractography indicated that these regions are consistent with the trajectories of the superior and inferior longitudinal fasciculi. In a second investigation, we assessed the effect of white matter damage on processing speed using voxel-based lesion-symptom mapping (VLSM) analysis of data from seventy-two patients with left-hemisphere strokes. Lesions in left parietal white matter, together with cortical lesions in supramarginal and angular gyri were associated with impaired performance. These findings suggest that cognitive processing speed, as assessed by the Digit-Symbol test, is closely related to the structural integrity of white matter tracts associated with parietal and temporal cortices and left middle frontal gyrus. Further, fiber tractography applied to VBM results and the patient findings suggest that the superior longitudinal fasciculus, a major tract subserving fronto-parietal integration, makes a prominent contribution to processing speed.
 
Article
The specific role of particular cerebral regions with regard to executive functions remains elusive. We conducted a functional magnetic resonance imaging (fMRI) study to segregate different network components underlying the Wisconsin Card Sorting Test (WCST), a test widely applied clinically to assess executive abilities. Three different test variants of the WCST, differing in task complexity (A > B > C), were contrasted with a high-level baseline condition (HLB). Cognitive subcomponents were extracted in a serial subtraction approach (A-C, A-B, B-C). Imaging data were further subjected to a correlational analysis with individual behavioral parameters. Contrasting A with the HLB revealed the entire neural network underlying WCST performance, including frontoparietal regions and the striatum. Further analysis showed that, within this network, right ventrolateral prefrontal cortex related to simple working memory operations, while right dorsolateral prefrontal cortex related to more complex/manipulative working memory operations. The rostral anterior cingulate cortex (ACC) and the temporoparietal junction bilaterally represented an attentional network for error detection. In contrast, activation of the caudal ACC and the right dorsolateral prefrontal cortex was associated with increased attentional control in the context of increasing demands of working memory and cognitive control. Non-frontal activations were found to be related to (uninstructed relative to instructed) set-shifting (cerebellum) and working memory representations (superior parietal cortex, retrosplenium). The data provide neural correlates for the different cognitive components involved in the WCST. They support a central role of the right dorsolateral prefrontal cortex in executive working memory operations and cognitive control functions but also suggest a functional dissociation of the rostral and caudal ACC in the implementation of attentional control.
 
Article
Brain maturation is a complex process that continues well beyond infancy, and adolescence is thought to be a key period of brain rewiring. To assess structural brain maturation from childhood to adulthood, we charted brain development in subjects aged 5 to 30 years using diffusion tensor magnetic resonance imaging, a novel brain imaging technique that is sensitive to axonal packing and myelination and is particularly adept at virtually extracting white matter connections. Age-related changes were seen in major white matter tracts, deep gray matter, and subcortical white matter, in our large (n=202), age-distributed sample. These diffusion changes followed an exponential pattern of maturation with considerable regional variation. Differences observed in developmental timing suggest a pattern of maturation in which areas with fronto-temporal connections develop more slowly than other regions. These in vivo results expand upon previous postmortem and imaging studies and provide quantitative measures indicative of the progression and magnitude of regional human brain maturation.
 
Article
Visualizing brain anatomy in vivo could provide insight into normal and pathophysiology. Here it is demonstrated that neuroarchitecture can be detected in the rodent brain using MRI after systemic MnCl2. Administration of MnCl2 leads to rapid T1 enhancement in the choroid plexus and circumventricular organs, which spreads to the CSF space in ventricles and periventricular tissue. After 1 day, there was MRI enhancement throughout the brain with high intensity in the pituitary, olfactory bulb, cortex, basal forebrain, hippocampus, basal ganglia, hypothalamus, amygdala, and cerebellum. Contrast obtained enabled visualization of specific features of neuroarchitecture. The arrowhead structure of the dentate gyrus as well as the CA1-CA3 region of the hippocampus and layers in cortex, cerebellum, as well as the olfactory bulb could be readily observed. Preliminary assignments of olfactory bulb layers, cortical layers in frontal and somatosensory cortex, and cerebellum were made. Systemic MnCl2 leads to MRI visualization of neuroarchitecture nondestructively.
 
Article
Brain connectivity datasets comprise networks of brain regions connected by anatomical tracts or by functional associations. Complex network analysis-a new multidisciplinary approach to the study of complex systems-aims to characterize these brain networks with a small number of neurobiologically meaningful and easily computable measures. In this article, we discuss construction of brain networks from connectivity data and describe the most commonly used network measures of structural and functional connectivity. We describe measures that variously detect functional integration and segregation, quantify centrality of individual brain regions or pathways, characterize patterns of local anatomical circuitry, and test resilience of networks to insult. We discuss the issues surrounding comparison of structural and functional network connectivity, as well as comparison of networks across subjects. Finally, we describe a Matlab toolbox (http://www.brain-connectivity-toolbox.net) accompanying this article and containing a collection of complex network measures and large-scale neuroanatomical connectivity datasets.
 
Article
Heavy marijuana use has well established long term consequences for cognition and mental health, but the effect on brain structure is less well understood. We used an MRI technique that is sensitive to the structural integrity of brain tissue combined with a white matter mapping tractography technique to investigate structural changes in the corpus callosum (CC). Diffusion tensor imaging (DTI) was obtained in eleven heavy marijuana users who started using marijuana in early adolescence and eleven age matched controls. Mean diffusivity (MD) and fractional anisotropy (FA) (which measure structural integrity and tract coherence, respectively) were analysed within the corpus callosum which was spatially defined using tractography and tract-based spatial statistics (TBSS). MD was significantly increased in marijuana users relative to controls in the region of the CC where white matter passes between the prefrontal lobes. This observation suggests impaired structural integrity affecting the fibre tracts of the CC and is in keeping with previous reports of altered and diversified activation patterns in marijuana users. There was a trend towards a positive correlation between MD and length of use suggesting the possibility of a cumulative effect of marijuana over time and that a younger age at onset of use may predispose individuals to structural white matter damage. Structural abnormalities revealed in the CC may underlie cognitive and behavioural consequences of long term heavy marijuana use.
 
Article
This paper reviews and compares individual voxel-wise thresholding methods for identifying active voxels in single-subject fMRI datasets. Different error rates are described which may be used to calibrate activation thresholds. We discuss methods which control each of the error rates at a prespecified level alpha, including simple procedures which ignore spatial correlation among the test statistics as well as more elaborate ones which incorporate this correlation information. The operating characteristics of the methods are shown through a simulation study, indicating that the error rate used has an important impact on the sensitivity of the thresholding method, but that accounting for correlation has little impact. Therefore, the simple procedures described work well for thresholding most single-subject fMRI experiments and are recommended. The methods are illustrated with a real bilateral finger tapping experiment.
 
Article
The catechol-O-methyltransferase (COMT) Val(108/158)Met polymorphism of the dopamine system is essential for prefrontal cortex processing capacity and efficiency. In addition, dopaminergic neurotransmission is also associated with the sensory gating phenomenon protecting the cerebral cortex from information overload. It is however unclear if COMT genotype as a predictor of prefrontal efficiency modulates sensory gating on the level of the auditory cortex, i.e. the gating of the auditory evoked P50 and N100 components. P50 and N100 gating and COMT Val(108/158)Met genotype were determined in 282 healthy subjects of German descent carefully screened for psychiatric or neurological disorders. A significant effect of the COMT genotype was observed for N100 gating (F=4.510, df=2, p=0.012) but not for P50 gating (F=0.376, df=2, p=0.687). Contrast analysis showed that Met/Met individuals had poorer N100 gating compared to Val/Met (F=-12.931, p=0.003) and the Val/Val individuals (F=-11.056, p=0.057). The results indicate that a high prefrontal efficiency as suggested by the COMT Met/Met genotype is associated with to a poor sensory gating of the N100 component. This would fit in a model where a high prefrontal processing capacity allows a pronounced afferent input of sensory information from the auditory cortex as reflected by a poor sensory gating. The more pronounced prefrontal contribution to the N100 compared to the P50 component may explain the exclusive genotype association with the N100 sensory gating. This preliminary model should be replicated and validated in future investigations.
 
Article
In this study we assessed the new glutamatergic ligand (11)C-ABP688 with regard to the following characteristics: (A) brain distribution, (B) first pass extraction fraction, (C) suitable model to describe tracer kinetics and (D) specificity for the mGlu5 receptor. These parameters were assessed using autoradiography and a beta-scintillator positioned in the striatum. The study included 13 male rats. In 2 animals cerebral blood flow was measured using H(2)(15)O. The (11)C-ABP688 data were analyzed using compartmental modeling. A two-tissue compartment model turned out to fit the data more adequately (parameters: K(1), k(2)('), k(3)('), k(4), total distribution volume DV(tot)=K(1)/k(2)(') (1+k(3)(')/k(4)) than a one-tissue compartment model. The autoradiographic studies revealed high uptake in hippocampus, striatum and cortex and low accumulation in thalamus and cerebellum. The uptake was markedly reduced following blockade with the mGlu5 antagonist M-MPEP. The first pass extraction fraction exceeded 85%. Baseline DV(tot) was 15.16+/-2.67 ml plasma/ml tissue and decreased by 56, 67 and 72% following blockade with 1, 2 and 6 mg/kg M-MPEP, respectively. These results show that (11)C-ABP688 is a promising PET ligand for the quantification of mGlu5 receptors in humans and animals. It readily crosses the blood-brain barrier and binds with high specificity to the mGlu5 receptor. The study furthermore demonstrates the usefulness of a beta-scintillator, if necessary in connection with autoradiography, to evaluate new receptor tracers.
 
Article
Cocaine abusers exhibit impairment of executive cognitive functions that are mediated by the frontal cortex. This work tested for structural (i.e., tissue composition) abnormalities that may underlie such performance deficits. Research participants were cocaine abusers (n = 14) abstinent for 20 days and a non-drug-using comparison group (n = 11), who underwent magnetic resonance imaging (T1-weighted scans of the brain). Gray matter and white matter tissue densities were determined using voxel-based morphometry with small volume correction based on a priori hypotheses derived from functional imaging of the same subjects. Cocaine abusers had significantly lower gray matter tissue density than did the non drug users in 10 of 13 small volumes analyzed in the frontal cortex [bilateral anterior cingulate gyrus (infragenual and perigenual regions) and medial orbitofrontal cortex and the lateral orbitofrontal cortex and middle/dorsal cingulate gyrus in the right hemisphere]. No group differences were found in white matter density of the frontal cortex. These results extend our previous findings of defective frontal cortical activation (indexed by cerebral blood flow) in cocaine abusers to include abnormalities in gray matter tissue density in the same frontal cortical regions.
 
The list of patients with JME and medication.
Article
The dopamine transporter (DAT) is of central interest in research on the pathophysiology and treatment of neuro-psychiatric disorders. [(11)C]PE2I is an established radioligand that provides high-contrast delineation of brain regions that are rich in DAT. The aim of the present PET study in eight patients with juvenile myoclonic epilepsy (JME) was to evaluate the kinetics of [(11)C]PE2I in the brain and to compare binding parameters with those of age-matched control subjects (n = 6). Each patient participated in 90-minute PET measurements with [(11)C]PE2I. Data were analyzed using kinetic compartment analyses with metabolite-corrected arterial plasma input and reference tissue models using the cerebellum as a reference region. The time-activity curves were well described by the two-tissue compartment model (2TCM) for the DAT-rich regions. The 2TCM with fixed K(1)/k(2) ratio derived from the cerebellum provided robust and reliable estimates of binding potential (BP(ND)) and total distribution volume (V(T)). The reference tissue models also provided robust estimates of BP(ND), although they gave lower BP(ND) values than the kinetic analysis. Compared with those of control subjects, we found that BP(ND) values obtained by all approaches were reduced in the midbrain of the patients with JME. The finding indicates impaired dopamine uptake in the midbrain of JME patients. The three-tissue compartment model could best describe uptake in the cerebellum, indicating that two kinetically distinguishable compartments exist in cerebellar tissue, which may correspond to nonspecific binding and the blood-brain barrier passing metabolite. The reference tissue models should be applied with better understanding of the biochemical nature of the radioligand and the reliability of these approaches.
 
Article
Unlabelled: Quantification of the binding of [11C]methylphenidate to the dopamine transporter (DAT) using positron emission tomography (PET) is often used to evaluate the integrity of dopaminergic neurons in the striatal regions of the brain. Over the past decade, many genetically engineered mouse models of human disease have been developed and have become particularly useful for the study of disease onset and progression over time. Quantitative imaging of small structures such as the mouse brain is especially challenging. Thus, the aims of this study were (1) to evaluate the accuracy of quantifying DAT binding using in vivo PET and (2) to examine the impact of different methodologies. Methods: Eight mice were scanned with [11C]methylphenidate under true or transient equilibrium conditions using a bolus and constant infusion protocol or a bolus injection protocol to evaluate the accuracy of the Logan graphical approach for [11C]methylphenidate imaging in mice. Displacement with unlabeled methylphenidate (0.1, 3 and 10 mg/kg) was used to verify specific binding. In a second experiment, 30 mice were lesioned by injection of 6-hydroxydopamine (6-OHDA) at doses of 0, 2 or 4 μg (n=10) into the right striatum to assess the dose-dependent correlation between the PET signal and dopaminergic degeneration. In addition, we performed test-retest experiments and used ex vivo autoradiography (AR) to validate the effect of partial volume on the accuracy of the [11C]methylphenidate PET quantification in the mouse striatum. Results: The binding potentials (BPND) calculated from the Logan graphical analysis under transient equilibrium conditions (1.03±0.1) were in excellent agreement with those calculated at true equilibrium (1.07±0.1). Displacement of specific binding with 0.1, 3 and 10mg/kg methylphenidate resulted in 38%, 77% and 81% transporter occupancy in the striatum. Intra-striatal injections of 6-OHDA caused a dose-dependent decrease in the specific binding of [11C]methylphenidate to the DAT in the striatum. The BPND was reduced by 49% and 61% after injection with 2 and 4 μg of 6-OHDA, respectively. The test-retest reproducibility was 6% in the healthy striatum and 27% in the lesioned striatum. In addition, only a small (15%) difference was found between the [11C]methylphenidate DVR-1 values determined by PET and AR on the healthy side, and no differences were observed on the lesioned side. Conclusion: The present work demonstrates for the first time that [11C]methylphenidate PET is useful for the quantification of striatal dopamine transporters at the dopaminergic nerve terminals in the mouse striatum; therefore, this marker may be used as a biomarker in genetically engineered mouse models of neurodegenerative disorders. However, only changes resulting in greater than 10% differences in BPND values can reliably be detected in vivo.
 
Article
The length polymorphism of the serotonin (5-HT) transporter gene promoter region has been implicated in altered 5-HT function and, in turn, neuropsychiatric illnesses, such as anxiety and depression. The nonhuman primate has been used as a model to study anxiety-related mechanisms in humans based upon similarities in behavior and the presence of a similar 5-HT transporter gene polymorphism. Stressful and threatening contexts in the nonhuman primate model have revealed 5-HT transporter genotype dependent differences in regional glucose metabolism. Using the rhesus monkey, we examined the extent to which serotonin transporter genotype is associated with 5-HT transporter binding in brain regions implicated in emotion-related pathology. Genotype data and high resolution PET scans were acquired in 29 rhesus (Macaca mulatta) monkeys. [C-11]DASB dynamic PET scans were acquired for 90 min in the anesthetized animals and images of distribution volume ratio (DVR) were created to serve as a metric of 5-HT transporter binding for group comparison based on a reference region method of analysis. Regional and voxelwise statistical analysis were performed with corrections for anatomical differences in gray matter probability, sex, age and radioligand mass. There were no significant differences when comparing l/l homozygotes with s-carriers in the regions of the brain implicated in anxiety and mood related illnesses (amygdala, striatum, thalamus, raphe nuclei, temporal and prefrontal cortex). There was a significant sex difference in 5-HT transporter binding in all regions with females having 18%-28% higher DVR than males. Because these findings are consistent with similar genotype findings in humans, this further strengthens the use of the rhesus model for studying anxiety-related neuropathologies.
 
Top-cited authors
Mark Jenkinson
  • University of Oxford
Bruce Fischl
  • Boston University
Christian Beckmann
  • Radboud University Medical Centre (Radboudumc)
Steve E Petersen
  • Washington University in St. Louis
Olaf Sporns
  • Indiana University Bloomington