Multimodal Neuroimaging in Schizophrenia: Description and Dissemination.

In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS).

Brain structure and verbal function across adulthood while controlling for cerebrovascular risks.

The development and decline of brain structure and function throughout adulthood is a complex issue, with cognitive aging trajectories influenced by a host of factors including cerebrovascular risk. Neuroimaging studies of age-related cognitive decline typically reveal a linear decrease in gray matter (GM) volume/density in frontal regions across adulthood. However, white matter (WM) tracts mature later than GM, particularly in regions necessary for executive functions and memory. Therefore, it was predicted that a middle-aged group (MC: 35-45 years) would perform best on a verbal working memory task and reveal greater regional WM integrity, compared with both young (YC: 18-25 years) and elder groups (EC: 60+ years). Diffusion tensor imaging (DTI) and magnetoencephalography (MEG) were obtained from 80 healthy participants. Objective measures of cerebrovascular risk and cognition were also obtained. As predicted, MC revealed best verbal working memory accuracy overall indicating some maturation of brain function between YC and MC. However, contrary to the prediction fractional anisotropy values (FA), a measure of WM integrity, were not greater in MC (i.e., there were no significant differences in FA between YC and MC but both groups showed greater FA than EC). An overall multivariate model for MEG ROIs showed greater peak amplitudes for MC and YC, compared with EC. Subclinical cerebrovascular risk factors (systolic blood pressure and blood glucose) were negatively associated with FA in frontal callosal, limbic, and thalamic radiation regions which correlated with executive dysfunction and slower processing speed, suggesting their contribution to age-related cognitive decline. Hum Brain Mapp 38:3472-3490, 2017. © 2017 Wiley Periodicals, Inc.

Middle cerebral artery blood flows by combining TCD velocities and MRA diameters: in vitro and in vivo validations.

Non-invasive transcranial Doppler (TCD) is widely used for blood velocity (BV, cm/sec) measurements in the human middle cerebral artery (MCA). MCABV measurements are accepted as linear with MCA blood flow (MCABF). Magnetic resonance angiography (MRA) provides measurements of MCA lumen diameters that can be combined with TCD MCABV to calculate MCABF (mL/min). We tested the precision and accuracy of this method against a flow phantom and in vivo proximal internal carotid artery blood flow (ICABF). In vitro precision (repeated measures) and accuracy (vs. time collection) gave correlations coefficients of 0.97 and 0.98, respectively (both p < 0.05). In vivo precision (repeated measures) and accuracy (vs. ICABF) gave correlation coefficients of 0.90 (left and right), 0.94 (left) and 0.93 (right) (all p < 0.05). Bilateral MCABF in 35 adults were similar (left, 168 ± 72 mL/min; right, 180 ± 69 mL/min; p > 0.05). Results suggest that blood velocity by TCD and lumen diameter by MRA can be combined to estimate absolute values of MCABF.

Functional connectivity in the developing brain: a longitudinal study from 4 to 9months of age.

We characterize the development of intrinsic connectivity networks (ICNs) from 4 to 9months of age with resting state magnetic resonance imaging performed on sleeping infants without sedative medication. Data is analyzed with independent component analysis (ICA). Using both low (30 components) and high (100 components) ICA model order decompositions, we find that the functional network connectivity (FNC) map is largely similar at both 4 and 9months. However at 9months the connectivity strength decreases within local networks and increases between more distant networks. The connectivity within the default-mode network, which contains both local and more distant nodes, also increases in strength with age. The low frequency power spectrum increases with age only in the posterior cingulate cortex and posterior default mode network. These findings are consistent with a general developmental pattern of increasing longer distance functional connectivity over the first year of life and raise questions regarding the developmental importance of the posterior cingulate at this age.

Characterization of a normal control group: are they healthy?

We examined the health of a control group (18-81years) in our aging study, which is similar to control groups used in other neuroimaging studies. The current study was motivated by our previous results showing that one third of the elder control group had moderate to severe white matter hyperintensities and/or cortical volume loss which correlated with poor performance on memory tasks. Therefore, we predicted that cardiovascular risk factors (e.g., hypertension, high cholesterol) within the control group would account for significant variance on working memory task performance. Fifty-five participants completed 4 verbal and spatial working memory tasks, neuropsychological exams, diffusion tensor imaging (DTI), and blood tests to assess vascular risk. In addition to using a repeated measures ANOVA design, a cluster analysis was applied to the vascular risk measures as a data reduction step to characterize relationships between conjoint risk factors. The cluster groupings were used to predict working memory performance. The results show that higher levels of systolic blood pressure were associated with: 1) poor spatial working memory accuracy; and 2) lower fractional anisotropy (FA) values in multiple brain regions. In contrast, higher levels of total cholesterol corresponded with increased accuracy in verbal working memory. An association between lower FA values and higher cholesterol levels were identified in different brain regions from those associated with systolic blood pressure. The conjoint risk analysis revealed that Risk Cluster Group 3 (the group with the greatest number of risk factors) displayed: 1) the poorest performance on the spatial working memory tasks; 2) the longest reaction times across both spatial and verbal memory tasks; and 3) the lowest FA values across widespread brain regions. Our results confirm that a considerable range of vascular risk factors are present in a typical control group, even in younger individuals, which have robust effects on brain anatomy and function. These results present a new challenge to neuroimaging studies both for defining a cohort from which to characterize 'normative' brain circuitry and for establishing a control group to compare with other clinical populations.

Regional cerebral blood flow in children from 3 to 5 months of age.

BACKGROUND AND PURPOSE: Understanding the relationship between brain and behavior in early childhood requires a probe of functional brain development. We report the first large study of regional CBF by use of arterial spin-labeling in young children. MATERIALS AND METHODS: Cerebral blood flow by use of arterial spin-labeling was measured in 61 healthy children between the ages of 3 and 5 months. Blood flow maps were parcellated into 8 broadly defined anatomic regions of each cerebral hemisphere. RESULTS: There was no sex effect; however, group analysis demonstrated significantly greater CBF in the sensorimotor and occipital regions compared with dorsolateral prefrontal, subgenual, and orbitofrontal areas (P < .0001). A significant age effect was also identified, with the largest increase in blood flow between 3 and 5 months occurring in the following regions: orbitofrontal (P < .009), subgenual (P < .002), and inferior occipital lobe (P = .001). CONCLUSIONS: These results are consistent with prior histologic studies demonstrating regional variation in brain maturation and suggest that arterial spin-labeling is sensitive to regional as well as age-related differences in CBF in young children.

Development and decline of memory functions in normal, pathological and healthy successful aging.

Many neuroimaging studies of age-related memory decline interpret resultant differences in brain activation patterns in the elderly as reflecting a type of compensatory response or regression to a simpler state of brain organization. Here we review a series of our own studies which lead us to an alternative interpretation, and highlights a couple of potential confounds in the aging literature that may act to increase the variability of results within age groups and across laboratories. From our perspective, level of cognitive functioning achieved by a group of elderly is largely determined by the health of individuals within this group. Individuals with a history of hypertension, for example, are likely to have multiple white matter insults which compromise cognitive functioning, independent of aging processes. The health of the elderly group has not been well-documented in most previous studies and elderly participants are rarely excluded, or placed into a separate group, due to health-related problems. In addition, recent results show that white matter tracts within the frontal and temporal lobes, regions critical for higher cognitive functions, continue to mature well into the 4th decade of life. This suggests that a young age group may not be the best control group for understanding aging effects on the brain since development is ongoing within this age range. Therefore, we have added a middle-age group to our studies in order to better understand normal development across the lifespan as well as effects of pathology on cognitive functioning in the aging brain.

Application of principal component analysis to distinguish patients with schizophrenia from healthy controls based on fractional anisotropy measurements.

Principal component analysis (PCA) is often used to reduce the dimension of data before applying more sophisticated data analysis methods such as non-linear classification algorithms or independent component analysis. This practice is based on selecting components corresponding to the largest eigenvalues. If the ultimate goal is separation of data in two groups, then these set of components need not have the most discriminatory power. We measured the distance between two such populations using Mahalanobis distance and chose the eigenvectors to maximize it, a modified PCA method, which we call the discriminant PCA (DPCA). DPCA was applied to diffusion tensor-based fractional anisotropy images to distinguish age-matched schizophrenia subjects from healthy controls. The performance of the proposed method was evaluated by the one-leave-out method. We show that for this fractional anisotropy data set, the classification error with 60 components was close to the minimum error and that the Mahalanobis distance was twice as large with DPCA, than with PCA. Finally, by masking the discriminant function with the white matter tracts of the Johns Hopkins University atlas, we identified left superior longitudinal fasciculus as the tract which gave the least classification error. In addition, with six optimally chosen tracts the classification error was zero.

Characterization of partially sintered ceramic powder compacts using fluorinated gas NMR imaging.

We use nuclear magnetic resonance (NMR) imaging of C2F6 gas to characterize porosity, mean pore size, and permeability of partially sintered ceramic (Y-TZP Yttria-stabilized tetragonal-zirconia polycrystal) samples. Conventional measurements of these parameters gave porosity values from 0.18 to 0.4, mean pore sizes from 10 nm to 40 nm, and permeability from 4 nm(2) to 25 nm(2). The NMR methods are based on relaxation time measurements (T(1)) and the time dependent diffusion coefficient D(Delta). The relaxation time of C2F6 gas is longer in pores than in bulk gas and it increases as the pore sizes decrease. NMR yielded accurate porosity values after correcting for surface adsorption effects. A model for T(1) dependence on pore size that accounts for collisions between gas molecules and walls as well as surface adsorption effects is proposed. The model fits the experimental data well. Finally, the long time limit of D(Delta)/D(o), where D(o) is the bulk gas diffusion coefficient is useful for measuring tortuosity, while the short time limit was not achieved experimentally and could not be used for calculating surface-area to volume (S/V) ratios.

Pulsed gradient spin echo nuclear magnetic resonance imaging of diffusion in granular flow

We derive the formalism to obtain spatial distributions of collisional correlation times for macroscopic particles undergoing granular flow from pulsed gradient spin echo nuclear magnetic resonance diffusion data. This is demonstrated with an example of axial motion in the shear flow regime of a 3D granular flow in a horizontal rotating cylinder at one rotation rate.

Imaging obstructed ventilation with NMR using inert fluorinated gases.

We partially obstructed the left bronchi of rats and imaged an inert insoluble gas, SF(6), in the lungs with NMR using a technique that clearly differentiates obstructed and normal ventilation. When the inhaled fraction of O(2) is high, SF(6) concentrates dramatically in regions of the lung with low ventilation-to-perfusion ratios (VA/Q); therefore, these regions are brighter in an image than where VA/Q values are normal or high. A second image, made when the inhaled fraction of O(2) is low, serves as a reference because the SF(6) fraction is nearly uniform, regardless of VA/Q. The quotient of the first and second images displays the low-VA/Q regions and is corrected for other causes of brightness variation. The technique may provide sufficient quantification of VA/Q to be a useful research tool. The noise in the quotient image is described by the probability density function for the quotient of two normal random variables. When the signal-to-noise ratio of the denominator image is >10, the signal-to-noise ratio of the quotient image is similar to that of the parent images and decreases with pixel value.

Correlation time and diffusion coefficient imaging: application to a granular flow system.

A parametric method for spatially resolved measurements for velocity autocorrelation functions, R(u)(tau) = , expressed as a sum of exponentials, is presented. The method is applied to a granular flow system of 2-mm oil-filled spheres rotated in a half-filled horizontal cylinder, which is an Ornstein-Uhlenbeck process with velocity autocorrelation function R(u)(tau) = e(- ||tau ||/tau(c)), where tau(c) is the correlation time and D = tau(c) is the diffusion coefficient. The pulsed-field-gradient NMR method consists of applying three different gradient pulse sequences of varying motion sensitivity to distinguish the range of correlation times present for particle motion. Time-dependent apparent diffusion coefficients are measured for these three sequences and tau(c) and D are then calculated from the apparent diffusion coefficient images. For the cylinder rotation rate of 2.3 rad/s, the axial diffusion coefficient at the top center of the free surface was 5.5 x 10(-6) m(2)/s, the correlation time was 3 ms, and the velocity fluctuation or granular temperature was 1.8 x 10(-3) m(2)/s(2). This method is also applicable to study transport in systems involving turbulence and porous media flows.

Transforming NMR data despite missing points.

Some NMR experiments produce data with several of the initial points missing. The inverse discrete Fourier transform (IDFT) assumes these points are present so the data cannot be so transformed without artifact-ridden results. This problem is often particularly severe when projection imaging with free-induction decays (FIDs). This paper compares recent methods for obtaining a projection from incomplete data and elaborates on their strengths and limitations. One method is to write the transform that would take the desired projection to the truncated data set, and then solve the matrix equation by singular value decomposition. A second replaces the missing data with zeros, so that an IDFT produces a projection with unwanted artifacts. Then one solves the matrix equation that takes the desired projection to the artifact-ridden projection. A third uses the same artifact-ridden projection, but fits the region outside the bandwidth of the sample with as many sinusoidal functions as there are missing data. The coefficients of these functions are estimates of the missing data, and the projection is obtained by transforming the completed FID or subtracting the extrapolation of the fitted curve from the region containing the object. We show that when all three methods are applicable, they theoretically produce the same result. They differ by ease of implementation and possibly by computational errors. They give a result similar to that of the previous method that iteratively corrects the FID and projection after repeated IDFTs and DFTs. We find that one can obtain a projection despite missing a substantial number of data.

Efficacy of recombinant human Hb by 31P-NMR during isovolemic total exchange transfusion.

The ability of recombinant human Hb (rHb1.1), which is being developed as an oxygen therapeutic, to support metabolism was measured by in vivo 31P-NMR surface coil spectroscopy of the rat abdomen in control animals and in animals subjected to isovolemic exchange transfusion to hematocrit of <3% with human serum albumin or 5 g/dl rHb1.1. No significant changes in metabolite levels were observed in control animals for up to 6 h. The albumin-exchange experiments, however, resulted in a more than eightfold increase in Pi and a 50% drop in phosphocreatine and ATP within 40 min. The tissue pH dropped from 7.4 to 6.8. The decrease in high-energy phosphates obeyed Michaelis-Menten kinetics, with a Michaelis-Menten constant of 3% as the hematocrit at which a 50% drop in high-energy phosphates was observed. Exchange transfusion with rHb1.1 resulted in no significant drop in high-energy phosphates, no rise in Pi, and no change in tissue pH from 7.35 +/- 0.15 for up to 5 h after exchange. By these criteria, rHb1.1 at a plasma Hb concentration of approximately 5 g/dl after total exchange transfusion was able to sustain energy metabolism of gut tissue at levels indistinguishable from control rats with a threefold higher total Hb level in erythrocytes.

Effect of head-down tilt on brain water distribution.

Vascular and tissue fluid dynamics in the microgravity of space environments is commonly simulated by head-down tilt (HDT). Previous reports have indicated that intracranial pressure and extracranial vascular pressures increase during acute HDT and may cause cerebral edema. Tissue water changes within the cranium are detectable by T2 magnetic resonance imaging. We obtained T2 images of sagittal slices from five subjects while they were supine and during -13 degrees HDT using a 1.5-Tesla whole-body magnet. The analysis of difference images demonstrated that HDT leads to a 21% reduction of T2 in the subarachnoid cerebrospinal fluid (CSF) compartment and a 11% reduction in the eyes, which implies a reduction of water content; no increase in T2 was observed in other brain regions that have been associated with cerebral edema. These findings suggest that water leaves the CSF and ocular compartments by exudation as a result of increased transmural pressure causing water to leave the cranium via the spinal CSF compartment or the venous circulation.

A programmable pre-emphasis system.

MRI systems often use magnetic field gradient and shim pulse-shaping networks (pre-emphasis) to correct for magnetic field distortions caused by eddy currents. A pre-emphasis system that uses up to 16 fixed resistor-capacitor (RC) time constants per channel with programmable amplitude coefficients is described. The magnetic fields induced by the pre-emphasis RC time constants serve as a set of basis functions for compensating eddy-current fields induced by the gradient set. The resultant time-varying magnetic field gradient accurately reflects the gradient specified by the pulse programmer. Reductions in eddy-current fields are demonstrated for actively shielded and unshielded gradient sets.

Imaging lungs using inert fluorinated gases.

Rat lungs were imaged by 19F projection MRI of hexafluoroethane, mixed with 20% oxygen to form the inhaled gas. The 3D image had 700 microm resolution, and the data took 4.3 h to acquire. Free induction decays were collected in the presence of steady magnetic field gradients in 686 different directions. To take advantage of fast relaxation (T1 = 5.9 +/- 0.2 ms), the repetition time was 5 ms. To eliminate signal loss from magnetic field inhomogeneities, data were collected within 2 ms of spin excitation (from 80 micros to 2 ms after the 42-micros pi/2 pulses). The singular value decomposition of the transform from frequency to time domain was used to obtain projections despite the absence of data during and immediately after the RF pulses. Inert fluorinated gas imaging may be less expensive than polarized noble gas imaging and is appropriate for imaging steady-state rather than transient gas concentrations.

Diffusion imaging with hyperpolarized 3He Gas

We used MRI of hyperpolarized 3He to demonstrate some novel aspects of gas diffusion. Two different techniques were used. First, a slice was burned into a one-dimensional image by inverting the spins in the slice and diffusion was studied by measuring the magnetization as it filled the depleted slice. A diffusion coefficient was determined by the fit of these data. Second, one-dimensional diffusion images were made using a Stejskal-Tanner PGSE method. This was done with and without a temperature gradient present, showing that the effect of temperature can be dynamically monitored by such diffusion images. Copyright 1997 Academic Press. Copyright 1997Academic Press

Changes in muscle proton transverse relaxation times and acidosis during exercise and recovery.

We studied changes in muscle proton (1H) transverse relaxation times (T2) by magnetic resonance imaging during exercise and compared these changes with alterations in muscle metabolism measured by phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Eleven subjects completed two trials of intermittent incremental forearm wrist flexion exercise requiring 30 contractions/min for 5 min, 7 min of recovery between stages, and 5-N load increments/stage. Between stages of the first trial, T2 images of muscle 1H were obtained. Muscle T2 increased from 27.3 +/- 1.1 (SD) ms at rest to 35.8 +/- 3.6 ms after volitional fatigue (P < 0.05), whereas less active wrist extensor muscle T2 remained unchanged (26.8 +/- 0.9 to 28.8 +/- 1.6 ms; P > 0.05). After localizing the predominant muscle recruited from the T2 images, subjects completed an identical trial at least 1 wk later but involving surface coil 31P-MRS of the T2-enhanced muscle to measure the H+ concentration ([H+]). Intramuscular [H+] of T2-enhancing muscle increased from 1.1 +/- 0.1 x 10(-7) M at rest to 4.1 +/- 2.0 x 10(-7) M after volitional fatigue. Both muscle T2 and intramuscular [H+] increased in a bimodal manner, with T2 increasing before muscle [H+] (P < 0.05). The correlation coefficient between the percent change in T2 and muscle [H+] during exercise was +0.74 (range 0.48-0.98; P < 0.05) and +0.47 during recovery. After 12 min of recovery, muscle [H+] decreased to 1.4 +/- 0.3 x 10(-7) M (P < 0.05), and T2 remained close to postexercise values (32.2 +/- 3.1 ms, P > 0.05). The data indicate that 1) the T2 increases during increases in exercise intensity are nonlinear, 2) the T2 increases during exercise are significantly correlated with increases in [H+], and 3) the slow recovery of T2 compared with [H+] indicates that [H+] has a minor contribution to the recovery in T2.

Alveolar ventilation to perfusion heterogeneity and diffusion impairment in a mathematical model of gas exchange.

This study describes a two-compartment model of pulmonary gas exchange in which alveolar ventilation to perfusion (VA/Q) heterogeneity and impairment of pulmonary diffusing capacity (D) are simultaneously taken into account. The mathematical model uses as input data measurements usually obtained in the lung function laboratory. It consists of two compartments and an anatomical shunt. Each compartment receives fractions of alveolar ventilation and blood flow. Mass balance equations and integration of Fick's law of diffusion are used to compute alveolar and blood O2 and CO2 values compatible with input O2 uptake and CO2 elimination. Two applications are presented. The first is a method to partition O2 and CO2 alveolar-arterial gradients into VA/Q and D components. The technique is evaluated in data of patients with chronic obstructive pulmonary disease (COPD). The second is a theoretical analysis of the effects of blood flow variation in alveolar and blood O2 partial pressures. The results show the importance of simultaneous consideration of D to estimate VA/Q heterogeneity in patients with diffusion impairment. This factor plays an increasing role in gas alveolar-arterial gradients as severity of COPD increases. Association of VA/Q heterogeneity and D may produce an increase of O2 arterial pressure with decreasing QT which would not be observed if only D were considered. We conclude that the presented computer model is a useful tool for description and interpretation of data from COPD patients and for performing theoretical analysis of variables involved in the gas exchange process.