K-t PCA accelerated in-plane balanced steady-state free precession phase-contrast (PC-SSFP) for all-in-one diastolic function evaluation.

PURPOSE: Diastolic function evaluation requires estimates of early and late diastolic mitral filling velocities (E and A) and of mitral annulus tissue velocity (e'). We aimed to develop an MRI method for simultaneous all-in-one diastolic function evaluation in a single scan by generating a 2D phase-contrast (PC) sequence with balanced steady-state free precession (bSSFP) contrast (PC-SSFP). E and A could then be measured with PC, and e' estimated by valve tracking on the magnitude images, using an established deep learning framework. METHODS: Our PC-SSFP used in-plane flow-encoding, with zeroth and first moment nulling over each TR. For further acceleration, different k-t principal component analysis (PCA) methods were investigated with both retrospective and prospective undersampling. PC-SSFP was compared to separate balanced SSFP cine and PC-gradient echo acquisitions in phantoms and in 10 healthy subjects. RESULTS: Phantom experiments showed that PC-SSFP measured accurate velocities compared to PC-gradient echo (r = 0.98 for a range of pixel-wise velocities -80 cm/s to 80 cm/s). In subjects, PC-SSFP generated high SNR and myocardium-blood contrast, and excellent agreement for E (limits of agreement [LOA] 0.8 ± 2.4 cm/s, r = 0.98), A (LOA 2.5 ± 4.1 cm/s, r = 0.97), and e' (LOA 0.3 ± 2.6 cm/s, r = 1.00), versus the standard methods. The best k-t PCA approach processed the complex difference data and substituted in raw k-space data. With prospective k-t PCA acceleration, higher frame rates were achieved (50 vs. 25 frames per second without k-t PCA), yielding a 13% higher e'. CONCLUSION: The proposed PC-SSFP method achieved all-in-one diastolic function evaluation.

Ketamine Effects on Energy Metabolism, Functional Connectivity and Working Memory in Healthy Humans.

Working memory (WM) is a crucial resource for temporary memory storage and the guiding of ongoing behavior. N-methyl-D-aspartate glutamate receptors (NMDARs) are thought to support the neural underpinnings of WM. Ketamine is an NMDAR antagonist that has cognitive and behavioral effects at subanesthetic doses. To shed light on subanesthetic ketamine effects on brain function, we employed a multimodal imaging design, combining gas-free calibrated functional magnetic resonance imaging (fMRI) measurement of oxidative metabolism (CMRO 2 ), resting-state cortical functional connectivity assessed with fMRI, and WM-related fMRI. Healthy subjects participated in two scan sessions in a randomized, double-blind, placebo-controlled design. Ketamine increased CMRO 2 and cerebral blood flow (CBF) in prefrontal cortex (PFC) and other cortical regions. However, resting-state cortical functional connectivity was not affected. Ketamine did not alter CBF-CMRO 2 coupling brain-wide. Higher levels of basal CMRO 2 were associated with lower task-related PFC activation and WM accuracy impairment under both saline and ketamine conditions. These observations suggest that CMRO 2 and resting-state functional connectivity index distinct dimensions of neural activity. Ketamine’s impairment of WM-related neural activity and performance appears to be related to its ability to produce cortical metabolic activation. This work illustrates the utility of direct measurement of CMRO 2 via calibrated fMRI in studies of drugs that potentially affect neurovascular and neurometabolic coupling.

HALO: A software tool for real-time head alignment in the MR scanner.

PURPOSE: MRI studies in human subjects often require multiple scanning sessions/visits. Changes in a subject's head position across sessions result in different alignment between brain tissues and the magnetic field which leads to changes in magnetic susceptibility. These changes can have considerable impacts on acquired signals. Head ALignment Optimization (HALO), a software tool was developed by the authors for active head alignment between sessions. METHODS: HALO provides real-time visual feedback of a subject's current head position relative to the position in a previous session. The tool was evaluated in a pilot sample of seven healthy human subjects. RESULTS: HALO was shown to enable subjects to actively align their head positions to the desired position of their initial sessions. The subjects were able to improve their head alignment significantly using HALO and achieved good alignment with their first session meeting stringent criteria similar to that used for within-run head motion (less than 2 mm translation or 2 degrees rotation in any direction from the desired position). Moreover, we found a negative correlation between the post-alignment rotation and similarity in inter-session BOLD patterns around the air-tissue interface near sinus which further highlighted the impact of tissue-field alignment on BOLD data quality. CONCLUSION: Utilization of HALO in longitudinal studies may help to improve data quality by ensuring the consistency of susceptibility gradients in brain tissues across sessions. HALO has been made publicly available.

Functional connectivity predicts changes in attention observed across minutes, days, and months.

The ability to sustain attention differs across people and changes within a single person over time. Although recent work has demonstrated that patterns of functional brain connectivity predict individual differences in sustained attention, whether these same patterns capture fluctuations in attention within individuals remains unclear. Here, across five independent studies, we demonstrate that the sustained attention connectome-based predictive model (CPM), a validated model of sustained attention function, generalizes to predict attentional state from data collected across minutes, days, weeks, and months. Furthermore, the sustained attention CPM is sensitive to within-subject state changes induced by propofol as well as sevoflurane, such that individuals show functional connectivity signatures of stronger attentional states when awake than when under deep sedation and light anesthesia. Together, these results demonstrate that fluctuations in attentional state reflect variability in the same functional connectivity patterns that predict individual differences in sustained attention.

Molecular characterization of AwSox2 from bivalve Anodonta woodiana: Elucidating its player in the immune response.

Sox2 is an embryonal stem cell Ag essential for early embryonic development, tissue homeostasis and immune regulation. In the current study, one complete Sox2 cDNA sequence was cloned from freshwater bivalve Anodonta woodiana and named AwSox2. Histological changes of testis derived from Bisphenol A (BPA) treatment were analyzed by hematoxylin and eosin staining. Expressions of AwSox2 derived from BPA, LPS and polyinosinic:polycytidylic (Poly I:C) challenge were measured by quantitative real-time PCR. The full-length cDNA of AwSox2 contained an open reading frame of 927 nucleotides bearing the typical structural features of Sox2 family. Obvious degeneration, irregular arrangement of spermatids, and clotted dead and intertwined spermatids were observed in BPA-treated groups. Administration of BPA could result in a dose-dependent up-regulation of AwSox2 expression in the male gonadal tissue of A. woodiana. In addition, expression of AwSox2 was significantly induced by LPS and Poly I:C treatment in the hepatopancreas, gill and hemocytes, compared with that of control group. These results indicated that up-regulations of AwSOx2 are closely related to apoptosis of spermatogonial stem cells derived from BPA treatment as well as enhancement of immune defense against LPS and Poly I:C challenge in A. woodiana.

Valvular imaging in the era of feature-tracking: A slice-following cardiac MR sequence to measure mitral flow.

BACKGROUND: In mitral valve dysfunction, noninvasive measurement of transmitral blood flow is an important clinical examination. Flow imaging of the mitral valve, however, is challenging, since it moves in and out of the image plane during the cardiac cycle. PURPOSE: To more accurately measure mitral flow, a slice-following MRI phase contrast sequence is proposed. This study aimed to implement such a sequence, validate its slice-following functionality in a phantom and healthy subjects, and test its feasibility in patients with mitral valve dysfunction. STUDY TYPE: Prospective. PHANTOM AND SUBJECTS: The slice-following functionality was validated in a cone-shaped phantom by measuring the depicted slice radius. Sixteen healthy subjects and 10 mitral valve dysfunction patients were enrolled at two sites. FIELD STRENGTH/SEQUENCE: 1.5T and 3T gradient echo cine phase contrast. ASSESSMENT: A single breath-hold retrospectively gated sequence using offline feature-tracking of the mitral valve was developed. Valve displacements were measured and imported to the scanner, allowing the slice position to change dynamically based on the cardiac phase. Mitral valve imaging was performed with slice-following and static imaging planes. Validation was performed by comparing mitral stroke volume with planimetric and aortic stroke volume. STATISTICAL TESTS: Measurements were compared using linear regression, Pearson's R, parametric paired t-tests, Bland-Altman analysis, and intraclass correlation coefficient (ICC). RESULTS: Phantom experiments confirmed accurate slice displacements. Slice-following was feasible in all subjects, yielding physiologically accurate mitral flow patterns. In healthy subjects, mitral and aortic stroke volumes agreed, with ICC = 0.72 and 0.90 for static and slice-following planes; with bias ±1 SDs 23.2 ± 13.2 mls and 8.4 ± 10.8 mls, respectively. Agreement with planimetry was stronger, with ICC = 0.84 and 0.96; bias ±1 SDs 13.7 ± 13.7 mls and -2.0 ± 8.8 mls for static and slice-following planes, respectively. DATA CONCLUSION: Slice-following outperformed the conventional sequence and improved the accuracy of transmitral flow, which is important for assessment of diastolic function and mitral regurgitation. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;51:1412-1421.

Dynamic-flip-angle ECG-gating with nuisance signal regression improves resting-state BOLD functional connectivity mapping by reducing cardiogenic noise.

PURPOSE: To investigate an ECG-gated dynamic-flip-angle BOLD sequence with improved robustness against cardiogenic noise in resting-state fMRI. METHODS: ECG-gating minimizes the cardiogenic noise but introduces T1 -dependent signal variation, which is minimized by combination of a dynamic-flip-angle technique and retrospective nuisance signal regression (NSR) using signals of white matter, CSF, and global average. The technique was studied with simulations in a wide range of T1 and B1 fields and phantom imaging with pre-programmed TR variations. Resting-state fMRI of 20 healthy subjects was acquired with non-gated BOLD (NG), ECG-gated constant-flip-angle BOLD (GCFA), ECG-gated BOLD with retrospective T1 -correction (GRC), and ECG-gated dynamic-flip-angle BOLD (GDFA), all processed by the same NSR method. GDFA was compared to alternative methods over temporal SNR (tSNR), seed-based connectivity, and whole-brain voxelwise connectivity based on intrinsic connectivity distribution (ICD). A previous large-cohort data set (N = 100) was used as a connectivity gold standard. RESULTS: Simulations and phantom imaging show substantial reduction of the T1 -dependent signal variation with GDFA alone, and further reduction with NSR. The resting-state study shows improved tSNR in the basal brain, comparing GDFA to NG, after both processed with NSR. Furthermore, GDFA significantly improved subcortical-subcortical and cortical-subcortical connectivity for several representative seeds and significantly improved ICD in the brainstem, thalamus, striatum, and prefrontal cortex, compared to the other 3 approaches. CONCLUSION: GDFA with NSR improves mapping of the resting-state functional connectivity of the basal-brain regions by reducing cardiogenic noise.

Magnetic Resonance Imaging of Shear Stress and Wall Thickness in Tissue-Engineered Vascular Grafts.

OBJECTIVES: Tissue-engineered vascular grafts (TEVGs) have demonstrated potential for treating congenital heart disease (CHD); however, quantitative imaging for tracking functional and structural remodeling of TEVGs has not been applied. Therefore, we evaluated the potential of magnetic resonance (MR) imaging for assessing TEVG wall shear stress (WSS) and wall thickness in a large animal model. METHODS: Cell-seeded (n = 3) or unseeded (n = 3) TEVGs were implanted as inferior vena cava interposition grafts in juvenile lambs. Six months following implantation, two-dimensional phase-contrast MR imaging was performed at 3 slice locations (proximal, middle, and distal) to assess normalized WSS (i.e., WSS-to-cross sectional area). T2-weighted MR imaging was performed to assess TEVG wall thickness. Histology was qualitatively assessed, whereas immunohistochemistry was semiquantitatively assessed for smooth muscle cells (αSMA), macrophage lineage cells (CD11b), and matrix metalloproteinase activity (MMP-2 and MMP-9). Picrosirius Red staining was performed to quantify collagen content. RESULTS: TEVG wall thickness was significantly higher for proximal, middle, and distal slices in unseeded versus cell-seeded grafts. Significantly higher WSS values existed for proximal versus distal slice locations for cell-seeded TEVGs, whereas no differences in WSS existed between slices for unseeded TEVGs. Additionally, no differences in WSS existed between cell-seeded and unseeded groups. Both groups demonstrated elastin formation, without vascular calcification. Unseeded TEVGs possessed greater content of smooth muscle cells when compared with cell-seeded TEVGs. No differences in macrophage, MMP activity, or collagen content existed between groups. CONCLUSION: MR imaging allows for in vivo assessment of functional and anatomical characteristics of TEVGs and may provide a nonionizing approach that is clinically translatable to children undergoing treatment for CHD.

Time course of clinical change following neurofeedback.

Neurofeedback - learning to modulate brain function through real-time monitoring of current brain state - is both a powerful method to perturb and probe brain function and an exciting potential clinical tool. For neurofeedback effects to be useful clinically, they must persist. Here we examine the time course of symptom change following neurofeedback in two clinical populations, combining data from two ongoing neurofeedback studies. This analysis reveals a shared pattern of symptom change, in which symptoms continue to improve for weeks after neurofeedback. This time course has several implications for future neurofeedback studies. Most neurofeedback studies are not designed to test an intervention with this temporal pattern of response. We recommend that new studies incorporate regular follow-up of subjects for weeks or months after the intervention to ensure that the time point of greatest effect is sampled. Furthermore, this time course of continuing clinical change has implications for crossover designs, which may attribute long-term, ongoing effects of real neurofeedback to the control intervention that follows. Finally, interleaving neurofeedback sessions with assessments and examining when clinical improvement peaks may not be an appropriate approach to determine the optimal number of sessions for an application.

Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial.

Importance: Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional target-engagement biomarkers for translation between preclinical and early-stage clinical studies. We evaluated the utility of 3 potential biomarkers-ketamine-evoked changes in the functional magnetic imaging (fMRI) blood oxygen level-dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (1H MRS), and task-based fMRI-for detecting ketamine-related alterations in brain glutamate. Objective: To identify measures with sufficient effect size and cross-site reliability to serve as glutamatergic target engagement biomarkers within early-phase clinical studies. Design, Setting, and Participants: This randomized clinical trial was conducted at an academic research institution between May 2014 and October 2015 as part of the National Institute of Mental Health-funded Fast-Fail Trial for Psychotic Spectrum Disorders project. All raters were blinded to study group. Healthy volunteers aged 18 to 55 years of either sex and free of significant medical or psychiatric history were recruited from 3 sites. Data were analyzed between November 2015 and December 2016. Interventions: Volunteers received either sequential ketamine (0.23 mg/kg infusion over 1 minute followed by 0.58 mg/kg/h infusion over 30 minutes and then 0.29 mg/kg/h infusion over 29 minutes) or placebo infusions. Main Outcomes and Measures: Ketamine-induced changes in pharmacoBOLD, 1H MRS, and task-based fMRI measures, along with symptom ratings. Measures were prespecified prior to data collection. Results: Of the 65 volunteers, 41 (63%) were male, and the mean (SD) age was 31.1 (9.6) years; 59 (91%) had at least 1 valid scan. A total of 53 volunteers (82%) completed both ketamine infusions. In pharmacoBOLD, a highly robust increase (Cohen d = 5.4; P < .001) in fMRI response was observed, with a consistent response across sites. A smaller but significant signal (Cohen d = 0.64; P = .04) was also observed in 1H MRS-determined levels of glutamate+glutamine immediately following ketamine infusion. By contrast, no significant differences in task-activated fMRI responses were found between groups. Conclusions and Relevance: These findings demonstrate robust effects of ketamine on pharmacoBOLD across sites, supporting its utility for definitive assessment of functional target engagement. Other measures, while sensitive to ketamine effects, were not sufficiently robust for use as cross-site target engagement measures. Trial Registration: clinicaltrials.gov Identifier: NCT02134951.

Multi-modal analysis of functional connectivity and cerebral blood flow reveals shared and unique effects of propofol in large-scale brain networks.

Anesthesia-induced changes in functional connectivity and cerebral blow flow (CBF) in large-scale brain networks have emerged as key markers of reduced consciousness. However, studies of functional connectivity disagree on which large-scale networks are altered or preserved during anesthesia, making it difficult to find a consensus amount studies. Additionally, pharmacological alterations in CBF could amplify or occlude changes in connectivity due to the shared variance between CBF and connectivity. Here, we used data-driven connectivity methods and multi-modal imaging to investigate shared and unique neural correlates of reduced consciousness for connectivity in large-scale brain networks. Rs-fMRI and CBF data were collected from the same subjects during an awake and deep sedation condition induced by propofol. We measured whole-brain connectivity using the intrinsic connectivity distribution (ICD), a method not reliant on pre-defined seed regions, networks of interest, or connectivity thresholds. The shared and unique variance between connectivity and CBF were investigated. Finally, to account for shared variance, we present a novel extension to ICD that incorporates cerebral blood flow (CBF) as a scaling factor in the calculation of global connectivity, labeled CBF-adjusted ICD). We observed altered connectivity in multiple large-scale brain networks including the default mode (DMN), salience, visual, and motor networks and reduced CBF in the DMN, frontoparietal network, and thalamus. Regional connectivity and CBF were significantly correlated during both the awake and propofol condition. Nevertheless changes in connectivity and CBF between the awake and deep sedation condition were only significantly correlated in a subsystem of the DMN, suggesting that, while there is significant shared variance between the modalities, changes due to propofol are relatively unique. Similar, but less significant, results were observed in the CBF-adjusted ICD analysis, providing additional evidence that connectivity differences were not fully explained by CBF. In conclusion, these results provide further evidence of alterations in large-scale brain networks are associated with reduced consciousness and suggest that different modalities capture unique aspects of these large scale changes.

Comparison of regional skeletal muscle tissue oxygenation in college athletes and sedentary control subjects using quantitative BOLD MR imaging.

Blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging permits noninvasive assessment of tissue oxygenation. We hypothesized that BOLD imaging would allow for regional evaluation of differences in skeletal muscle oxygenation between athletes and sedentary control subjects, and dynamic BOLD responses to ischemia (i.e., proximal cuff occlusion) and reactive hyperemia (i.e., rapid cuff deflation) would relate to lower extremity function, as assessed by jumping ability. College football athletes (linemen, defensive backs/wide receivers) were compared to sedentary healthy controls. BOLD signal of the gastrocnemius, soleus, anterior tibialis, and peroneus longus was assessed for peak hyperemic value (PHV), time to peak (TTP), minimum ischemic value (MIV), and time to recovery (TTR). Significantly higher PHVs were identified in athletes versus controls for the gastrocnemius (linemen, 15.8 ± 9.1%; defensive backs/wide receivers, 17.9 ± 5.1%; controls, 7.4 ± 3.5%), soleus (linemen, 25.9 ± 11.5%; backs/receivers, 22.0 ± 9.4%; controls, 12.9 ± 5.8%), and anterior tibialis (linemen, 12.8 ± 5.3%; backs/receivers, 12.6 ± 3.9%; controls, 7.7 ± 4.0%), whereas no differences in PHV were found for the peroneus longus (linemen, 14.1 ± 6.9%; backs/receivers, 11.7 ± 4.6%; controls, 9.0 ± 4.9%). In all subject groups, the gastrocnemius and soleus muscles exhibited the lowest MIVs during cuff occlusion. No differences in TTR were found between muscles for any subject group. PHV of the gastrocnemius muscle was significantly and positively related to maximal vertical (r = 0.56, P = 0.002) and broad jump (r = 0.47, P = 0.01). These results suggest that BOLD MR imaging is a useful noninvasive tool for evaluating differences in tissue oxygenation of specific muscles between active and sedentary individuals, and peak BOLD responses may relate to functional capacity.

Association of Thalamic Dysconnectivity and Conversion to Psychosis in Youth and Young Adults at Elevated Clinical Risk.

IMPORTANCE: Severe neuropsychiatric conditions, such as schizophrenia, affect distributed neural computations. One candidate system profoundly altered in chronic schizophrenia involves the thalamocortical networks. It is widely acknowledged that schizophrenia is a neurodevelopmental disorder that likely affects the brain before onset of clinical symptoms. However, no investigation has tested whether thalamocortical connectivity is altered in individuals at risk for psychosis or whether this pattern is more severe in individuals who later develop full-blown illness. OBJECTIVES: To determine whether baseline thalamocortical connectivity differs between individuals at clinical high risk for psychosis and healthy controls, whether this pattern is more severe in those who later convert to full-blown illness, and whether magnitude of thalamocortical dysconnectivity is associated with baseline prodromal symptom severity. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, 2-year follow-up, case-control study, we examined 397 participants aged 12-35 years of age (243 individuals at clinical high risk of psychosis, of whom 21 converted to full-blown illness, and 154 healthy controls). The baseline scan dates were January 15, 2010, to April 30, 2012. MAIN OUTCOMES AND MEASURES: Whole-brain thalamic functional connectivity maps were generated using individuals' anatomically defined thalamic seeds, measured using resting-state functional connectivity magnetic resonance imaging. RESULTS: Using baseline magnetic resonance images, we identified thalamocortical dysconnectivity in the 243 individuals at clinical high risk for psychosis, which was particularly pronounced in the 21 participants who converted to full-blown illness. The pattern involved widespread hypoconnectivity between the thalamus and prefrontal and cerebellar areas, which was more prominent in those who converted to full-blown illness (t(173) = 3.77, P < .001, Hedge g = 0.88). Conversely, there was marked thalamic hyperconnectivity with sensory motor areas, again most pronounced in those who converted to full-blown illness (t(173) = 2.85, P < .001, Hedge g = 0.66). Both patterns were significantly correlated with concurrent prodromal symptom severity (r = 0.27, P < 3.6 × 10(-8), Spearman ρ = 0.27, P < 4.75 × 10(-5), 2-tailed). CONCLUSIONS AND RELEVANCE: Thalamic dysconnectivity, resembling that seen in schizophrenia, was evident in individuals at clinical high risk for psychosis and more prominently in those who later converted to psychosis. Dysconnectivity correlated with symptom severity, supporting the idea that thalamic connectivity may have prognostic implications for risk of conversion to full-blown illness.

GABA, resting-state connectivity and the developing brain.

BACKGROUND: Preclinical data demonstrate that gamma-aminobutyric acid (GABA) interneurons initiate connectivity in the developing brain. OBJECTIVES: The goal of this study was to compare GABA concentration and its relationship to functional connectivity in the brains of term and preterm infants at term-equivalent age. METHODS: Infants received both magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) scans at term-equivalent age. Whole brain functional connectivity MRI data using intrinsic connectivity distribution maps were compared to identify areas with differences in resting-state functional connectivity between the preterm and term control groups. MRS measured concentrations of GABA, glutamate, N-acetyl-aspartate (NAA) and choline; NAA/choline was then calculated for comparison between the 2 groups. RESULTS: Preterm infants had lower right frontal GABA and glutamate concentrations than term controls and showed a significantly different relationship between connectivity and GABA concentration in the right frontal lobe. Preterm infants had a positive correlation between GABA concentration and connectivity, while term controls demonstrated a negative correlation between these two developmentally regulated parameters. CONCLUSION: These results suggest that regional GABA concentrations are associated with normal and altered neonatal resting-state connectivity.

Reliability of functional magnetic resonance imaging activation during working memory in a multi-site study: analysis from the North American Prodrome Longitudinal Study.

Multi-site neuroimaging studies offer an efficient means to study brain functioning in large samples of individuals with rare conditions; however, they present new challenges given that aggregating data across sites introduces additional variability into measures of interest. Assessing the reliability of brain activation across study sites and comparing statistical methods for pooling functional data are critical to ensuring the validity of aggregating data across sites. The current study used two samples of healthy individuals to assess the feasibility and reliability of aggregating multi-site functional magnetic resonance imaging (fMRI) data from a Sternberg-style verbal working memory task. Participants were recruited as part of the North American Prodrome Longitudinal Study (NAPLS), which comprises eight fMRI scanning sites across the United States and Canada. In the first study sample (n=8), one participant from each home site traveled to each of the sites and was scanned while completing the task on two consecutive days. Reliability was examined using generalizability theory. Results indicated that blood oxygen level-dependent (BOLD) signal was reproducible across sites and was highly reliable, or generalizable, across scanning sites and testing days for core working memory ROIs (generalizability ICCs=0.81 for left dorsolateral prefrontal cortex, 0.95 for left superior parietal cortex). In the second study sample (n=154), two statistical methods for aggregating fMRI data across sites for all healthy individuals recruited as control participants in the NAPLS study were compared. Control participants were scanned on one occasion at the site from which they were recruited. Results from the image-based meta-analysis (IBMA) method and mixed effects model with site covariance method both showed robust activation in expected regions (i.e. dorsolateral prefrontal cortex, anterior cingulate cortex, supplementary motor cortex, superior parietal cortex, inferior temporal cortex, cerebellum, thalamus, basal ganglia). Quantification of the similarity of group maps from these methods confirmed a very high (96%) degree of spatial overlap in results. Thus, brain activation during working memory function was reliable across the NAPLS sites and both the IBMA and mixed effects model with site covariance methods appear to be valid approaches for aggregating data across sites. These findings indicate that multi-site functional neuroimaging can offer a reliable means to increase power and generalizability of results when investigating brain function in rare populations and support the multi-site investigation of working memory function in the NAPLS study, in particular.

Non-invasive quantification of absolute cerebral blood volume during functional activation applicable to the whole human brain.

PURPOSE: Cerebral blood volume (CBV) changes in many diverse pathologic conditions, and in response to functional challenges along with changes in blood flow, blood oxygenation, and the cerebral metabolic rate of oxygen. The feasibility of a new method for non-invasive quantification of absolute cerebral blood volume that can be applicable to the whole human brain was investigated. METHODS: Multi-slice data were acquired at 3 T using a novel inversion recovery echo planar imaging (IR-EPI) pulse sequence with varying contrast weightings and an efficient rotating slice acquisition order, at rest and during visual activation. A biophysical model was used to estimate absolute cerebral blood volume at rest and during activation, and oxygenation during activation, on data from 13 normal human subjects. RESULTS: Cerebral blood volume increased by 21.7% from 6.6 ± 0.8 mL/100 mL of brain parenchyma at rest to 8.0 ± 1.3 mL/100 mL of brain parenchyma in the occipital cortex during visual activation, with average blood oxygenation of 84 ± 2.1% during activation, comparing well with literature. CONCLUSION: The method is feasible, and could foster improved understanding of the fundamental physiological relationship between neuronal activity, hemodynamic changes, and metabolism underlying brain activation; complement existing methods for estimating compartmental changes; and potentially find utility in evaluating vascular health.

Noninvasive MRI measurement of the absolute cerebral blood volume-cerebral blood flow relationship during visual stimulation in healthy humans.

PURPOSE: The relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF) underlies blood oxygenation level-dependent functional MRI signal. This study investigates the potential for improved characterization of the CBV-CBF relationship in humans, and examines sex effects as well as spatial variations in the CBV-CBF relationship. METHODS: Healthy subjects were imaged noninvasively at rest and during visual stimulation, constituting the first MRI measurement of the absolute CBV-CBF relationship in humans with complete coverage of the functional areas of interest. RESULTS: CBV and CBF estimates were consistent with the literature, and their relationship varied both spatially and with sex. In a region of interest with stimulus-induced activation in CBV and CBF at a significance level of the P < 0.05, a power function fit resulted in CBV = 2.1 CBF(0.32) across all subjects, CBV = 0.8 CBF(0.51) in females and CBV = 4.4 CBF(0.15) in males. Exponents decreased in both sexes as ROIs were expanded to include less significantly activated regions. CONCLUSION: Consideration for potential sex-related differences, as well as regional variations under a range of physiological states, may reconcile some of the variation across literature and advance our understanding of the underlying cerebrovascular physiology.

Reliability of neuroanatomical measurements in a multisite longitudinal study of youth at risk for psychosis.

Multisite longitudinal neuroimaging designs are used to identify differential brain structural change associated with onset or progression of disease. The reliability of neuroanatomical measurements over time and across sites is a crucial aspect of power in such studies. Prior work has found that while within-site reliabilities of neuroanatomical measurements are excellent, between-site reliability is generally more modest. Factors that may increase between-site reliability include standardization of scanner platform and sequence parameters and correction for between-scanner variations in gradient nonlinearities. Factors that may improve both between- and within-site reliability include use of registration algorithms that account for individual differences in cortical patterning and shape. In this study 8 healthy volunteers were scanned twice on successive days at 8 sites participating in the North American Prodrome Longitudinal Study (NAPLS). All sites employed 3 Tesla scanners and standardized acquisition parameters. Site accounted for 2 to 30% of the total variance in neuroanatomical measurements. However, site-related variations were trivial (<1%) among sites using the same scanner model and 12-channel coil or when correcting for between-scanner differences in gradient nonlinearity and scaling. Adjusting for individual differences in sulcal-gyral geometries yielded measurements with greater reliabilities than those obtained using an automated approach. Neuroimaging can be performed across multiple sites at the same level of reliability as at a single site, achieving within- and between-site reliabilities of 0.95 or greater for gray matter density in the majority of voxels in the prefrontal and temporal cortical surfaces as well as for the volumes of most subcortical structures.

A graphics processing unit accelerated motion correction algorithm and modular system for real-time fMRI.

Real-time functional magnetic resonance imaging (rt-fMRI) has recently gained interest as a possible means to facilitate the learning of certain behaviors. However, rt-fMRI is limited by processing speed and available software, and continued development is needed for rt-fMRI to progress further and become feasible for clinical use. In this work, we present an open-source rt-fMRI system for biofeedback powered by a novel Graphics Processing Unit (GPU) accelerated motion correction strategy as part of the BioImage Suite project ( www.bioimagesuite.org ). Our system contributes to the development of rt-fMRI by presenting a motion correction algorithm that provides an estimate of motion with essentially no processing delay as well as a modular rt-fMRI system design. Using empirical data from rt-fMRI scans, we assessed the quality of motion correction in this new system. The present algorithm performed comparably to standard (non real-time) offline methods and outperformed other real-time methods based on zero order interpolation of motion parameters. The modular approach to the rt-fMRI system allows the system to be flexible to the experiment and feedback design, a valuable feature for many applications. We illustrate the flexibility of the system by describing several of our ongoing studies. Our hope is that continuing development of open-source rt-fMRI algorithms and software will make this new technology more accessible and adaptable, and will thereby accelerate its application in the clinical and cognitive neurosciences.

Does baseline cerebral blood flow affect task-related blood oxygenation level dependent response in schizophrenia?

BACKGROUND: Experimental changes in resting cerebral blood flow (CBF) affect task-related blood oxygenation level dependent (BOLD) responses. Since patients with schizophrenia have been shown to have abnormal resting CBF, we sought to determine whether differences between patients and healthy controls in resting CBF contribute to group differences in BOLD response. METHODS: BOLD images were acquired in nineteen patients and twenty healthy controls looking at photographs of faces, and resting CBF was measured by arterial spinning labeling. Resting CBF was then used to adjust group differences in task-related BOLD signal increases in linear models. RESULTS: Patients had different resting CBF from healthy controls in right basal ganglion and bilateral thalami. Associations between resting CBF and delta BOLD were evident in bilateral prefrontal areas, visual processing areas and right fusiform gyrus. Other areas showed significant three-way interactions among group, delta BOLD and resting CBF. Incorporating resting CBF when modeling group differences in BOLD responses identified areas of group differences in task-related delta BOLD response that were not evident in simple group contrasts. These were in right inferior frontal cortex, left insula, left middle frontal cortex and bilateral frontal poles. CONCLUSION: Adjusting for inter-group differences in resting CBF altered inter-group differences in task-related BOLD response in some areas, suggesting that assessing resting CBF in task-related BOLD studies could increase sensitivity and validity. In multiple regions, the relationship between resting CBF and task-related signal increases in BOLD differed between patients and controls, providing new evidence of possible metabolic and/or vascular pathology.