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Background Neonatal abstinence syndrome (NAS) is a significant problem. Opioid withdrawal induces oxidative stress and disrupts glutamate and glutathione homeostasis. We hypothesized that N-acetylcysteine (NAC) administered during acute opioid withdrawal in neonatal rats would decrease withdrawal behaviors and normalize CNS glutathione and glutamate. Methods Osmotic minipumps with methadone (opioid dependent, OD) and saline (Sham) were implanted into Sprague Dawley dams 7 days prior to delivery. Pups were randomized to receive either naloxone plus saline or NAC (50–100 mg/kg), administered on postnatal day (PND) 7. We performed MR spectroscopy on PND6–7 before, 30 min, and 120 min after withdrawal. On PND7, we assessed withdrawal behaviors for 90 min after naloxone administration and summed scores during peak withdrawal period. Results Mean summed behavioral scores were significantly different between groups (χ2 (2) = 10.49, p = 0.005) but not different between NAC/NAL/OD and Sham (p = 0.14): SAL/NAL/OD = 17.2 ± 4.2 (n = 10); NAC/NAL/OD = 11.3 ± 5.6 (n = 9); Sham = 6.5 ± 0.6 (n = 4). SAL/NAL/OD pups had decreased glutathione at 120 min (p = 0.01), while NAC/NAL/OD pups maintained pre-withdrawal glutathione (p = 0.26). Conclusion In antenatal OD, NAC maintains CNS glutathione and mitigates acute opioid withdrawal in neonatal rats. This is the first study to demonstrate acute opioid withdrawal neurochemical changes in vivo in neonatal OD. NAC is a potential novel treatment for NAS.

N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg/kg q12h, 0.03 mg/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24–48 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.

Although the neurotransmitters/modulators glutamate and, more recently, glycine have been implicated in the development and maintenance of Alcohol Use Disorder (AUD) in preclinical research, human proton magnetic resonance spectroscopy ((1)H-MRS) studies have focused solely on the measurement of glutamate. The purpose of the present analysis was to examine the relative associations of brain glutamate and glycine levels with recent heavy drinking in 41 treatment naïve individuals with AUD using (1)H-MRS. The present study is the first that we are aware of to report in vivo brain glycine levels from an investigation of addiction. Dorsal Anterior Cingulate Cortex (dACC) glutamate and glycine concentration estimates were obtained using Two-Dimensional J-Resolved Point Resolved Spectroscopy at 3 Tesla, and past 2-week summary estimates of alcohol consumption were assessed via the Timeline Followback method. Glutamate (β= −0.44, t= −3.09, p= 0.004) and glycine (β= −0.68, t= −5.72, p< 0.001) were each significantly, inversely associated with number of heavy drinking days when considered alone. However, when both variables were simultaneously entered into a single regression model, the effect of glutamate was no longer significant (β= −0.11, t= −0.81, p= 0.42) whereas the effect of glycine remained significant (β= −0.62, t= −4.38, p< 0.001). The present study extends the literature by demonstrating a unique, inverse association of brain glycine levels with recent heavy drinking in treatment naïve individuals with AUD. If replicated and extended, these data could lead to enhanced knowledge of how glycinergic systems change with alcohol consumption and AUD progression leading to pharmacological interventional/preventative strategies that modulate brain glycine levels.

An 11–25% increase in total ventricular volume has been documented in astronauts following spaceflight on the ISS. Given the approximately 2-year time interval between pre- and post-flight MRI, it is unknown if ventricular enlargement simply reflects normal aging or is unique to spaceflight exposure. Therefore, we compared percent ventricular volume change per year (PVVC/yr) documented on pre- to post-flight MRI in a group of NASA ISS astronauts (n = 18, 16.7% women, mean age (SD) 48.43 (4.35) years) with two groups who underwent longitudinal MRI: (1.) healthy age- and sex-matched adults (n = 18, 16.7% women, mean age (SD) 51.26 (3.88) years), and (2.) healthy older adults (n = 79, 16.5% women, mean age (SD) 73.26 (5.34) years). The astronauts, who underwent a mean (SD) 173.4 (51.3) days in spaceflight, showed a greater increase in PVVC/yr than the control (6.86 vs 2.23%, respectively, p

Perception and cognition in the brain are naturally characterized as spatiotemporal processes. Decision-making, for example, depends on coordinated patterns of neural activity cascading across the brain, running in time from stimulus to response and in space from primary sensory regions to the frontal lobe. Measuring this cascade is key to developing an understanding of brain function. Here we report on a novel methodology that employs multi-modal imaging for inferring this cascade in humans at unprecedented spatiotemporal resolution. Specifically, we develop an encoding model to link simultaneously measured electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) signals to infer high-resolution spatiotemporal brain dynamics during a perceptual decision. After demonstrating replication of results from the literature, we report previously unobserved sequential reactivation of a substantial fraction of the pre-response network whose magnitude correlates with a proxy for decision confidence. Our encoding model, which temporally tags BOLD activations using time localized EEG variability, identifies a coordinated and spatially distributed neural cascade that is associated with a perceptual decision. In general the methodology illuminates complex brain dynamics that would otherwise be unobservable using fMRI or EEG acquired separately.

Background and purposeCurrently, there is neither a standard protocol for vessel wall MR imaging of intracranial atherosclerotic disease (ICAD) nor a gold standard phantom to compare MR sequences. In this study, a plaque phantom is developed and characterized that provides a platform for establishing a uniform imaging approach for ICAD.Materials and methodsA patient specific injection mold was 3D printed to construct a geometrically accurate ICAD phantom. Polyvinyl alcohol hydrogel was infused into the core shell mold to form the stenotic artery. The ICAD phantom incorporated materials mimicking a stenotic vessel and plaque components, including fibrous cap and lipid core. Two phantoms were scanned using high resolution cone beam CT and compared with four different 3 T MRI systems across eight different sites over a period of 18 months. Inter-phantom variability was assessed by lumen dimensions and contrast to noise ratio (CNR).ResultsQuantitative evaluation of the minimum lumen radius in the stenosis showed that the radius was on average 0.80 mm (95% CI 0.77 to 0.82 mm) in model 1 and 0.77 mm (95% CI 0.74 to 0.81 mm) in model 2. The highest CNRs were observed for comparisons between lipid and vessel wall. To evaluate manufacturing reproducibility, the CNR variability between the two models had an average absolute difference of 4.31 (95% CI 3.82 to 5.78). Variation in CNR between the images from the same scanner separated by 7 months was 2.5–6.2, showing reproducible phantom durability.ConclusionsA plaque phantom composed of a stenotic vessel wall and plaque components was successfully constructed for multicenter high resolution MRI standardization.

BACKGROUND AND PURPOSE: Widespread brain structural changes are seen following extended spaceflight missions. The purpose of this study was to investigate whether these structural changes are associated with alterations in motor or cognitive function. MATERIALS AND METHODS: Brain MR imaging scans of National Aeronautics and Space Administration astronauts were retrospectively analyzed to quantify pre- to postflight changes in brain structure. Local structural changes were assessed using the Jacobian determinant. Structural changes were compared with clinical findings and cognitive and motor function. RESULTS: Long-duration spaceflights aboard the International Space Station, but not short-duration Space Shuttle flights, resulted in a significant increase in total ventricular volume (10.7% versus 0%, P < .001, n = 12 versus n = 7). Total ventricular volume change was significantly associated with mission duration (r = 0.72, P = .001, n = 19) but negatively associated with age (r = −0.48, P = .048, n = 19). Long-duration spaceflights resulted in significant crowding of brain parenchyma at the vertex. Pre- to postflight structural changes of the left caudate correlated significantly with poor postural control; and the right primary motor area/midcingulate correlated significantly with a complex motor task completion time. Change in volume of 3 white matter regions significantly correlated with altered reaction times on a cognitive performance task (bilateral optic radiations, splenium of the corpus callosum). In a post hoc finding, astronauts who developed spaceflight-associated neuro-ocular syndrome demonstrated smaller changes in total ventricular volume than those who did not (12.8% versus 6.5%, n = 8 versus n = 4). CONCLUSIONS: While cautious interpretation is appropriate given the small sample size and number of comparisons, these findings suggest that brain structural changes are associated with changes in cognitive and motor test scores and with the development of spaceflight-associated neuro-optic syndrome.

Purpose Approximately 2 to 4% of the US population have been estimated to seek treatment for temporomandibular symptoms, predominately women. The study purpose was to determine whether sex-specific differences in temporomandibular morphometry result from scaling with sex differences in skull size and shape or intrinsic sex-specific differences. Materials and Methods A total of 22 (11 male [aged 74.5 ± 9.1 years]; 11 female [aged 73.6 ± 12.8 years]) human cadaveric heads with no history of temporomandibular disc derangement underwent cone beam computed tomography and high-resolution magnetic resonance imaging scanning to determine 3-dimensional cephalometric parameters and temporomandibular morphometric outcomes. Regression models between morphometric outcomes and cephalometric parameters were developed, and intrinsic sex-specific differences in temporomandibular morphometry normalized by cephalometric parameters were determined. Subject-specific finite element (FE) models of the extreme male and extreme female conditions were developed to predict variations in articular disc stress–strain under the same joint loading. Results In some cases, sex differences in temporomandibular morphometric parameters could be explained by linear scaling with skull size and shape; however, scaling alone could not fully account for some differences between sexes, indicating intrinsic sex-specific differences. The intrinsic sex-specific differences in temporomandibular morphometry included an increased condylar medial length and mediolateral disc lengths in men and a longer anteroposterior disc length in women. Considering the extreme male and female temporomandibular morphometry observed in the present study, subject-specific FE models resulted in sex differences, with the extreme male joint having a broadly distributed stress field and peak stress of 5.28 MPa. The extreme female joint had a concentrated stress field and peak stress of 7.37 MPa. Conclusions Intrinsic sex-specific differences independent of scaling with donor skull size were identified in temporomandibular morphometry. Understanding intrinsic sex-specific morphometric differences is critical to determining the temporomandibular biomechanics given the effect of anatomy on joint contact mechanics and stress–strain distributions and requires further study as one potential factor for the increased predisposition of women to temporomandibular disc derangement.

Proton Magnetic Resonance Spectroscopy ((1)H-MRS) studies have demonstrated abnormal levels of a variety of neurometabolites in treatment-seeking individuals with moderate-severe Alcohol Use Disorder (AUD) following acute withdrawal. In contrast, few studies have investigated neurochemical changes across early abstinence in less-severe, treatment-naïve AUD. The present study, which represents the primary report of a research grant from ABMRF/The Alcohol Research Fund, measured dorsal anterior cingulate cortex (dACC) GABA, glutamate, and glutamine levels in treatment-naïve AUD (n=23) via three (1)H-MRS scans spaced across a planned week of abstinence from alcohol. In addition to AUD participants, twelve light drinkers completed two scans, separated by 48 hours, to ensure that results in AUD were not produced by between-scan differences other than abstinence from alcohol. (1)H-MRS spectra were acquired in dACC at each scan using 2D J-resolved Point Resolved Spectroscopy. Linear mixed modeling results demonstrated a significant increase in GABA, but not glutamate or glutamine (ps=0.237–0.626), levels between scans 1 and 2 (+8.88%, p = 0.041), with no difference between scans 2 and 3 (+1.00%, p = 0.836), in AUD but not LD (F=1.24, p=0.290) participants. Exploratory regression analyses tentatively revealed a number of significant prospective associations between changes in glutamine levels and heavy drinking, craving and withdrawal symptoms. Most notably, the present study demonstrated return from abnormally-low to normal GABA levels in treatment-naïve AUD within 3d of their last drink; the pattern of results was consistent with glutamate and glutamine disturbances being exclusive to relatively more-severe AUD.

Little attention has been paid to relating MRS outputs of vendor‐supplied platforms to those from research software. This comparison is crucial to advance MRS as a clinical prognostic tool for disease or injury, recovery, and outcome. The work presented here investigates the agreement between metabolic ratios reported from vendor‐provided and LCModel fitting algorithms using MRS data obtained on Siemens 3 T TIM Trio and 3 T Skyra MRI scanners in a total of 55 premature infants and term neonates with hypoxic ischemic encephalopathy (HIE). We compared peak area ratios in single voxels placed in basal ganglia (BG) and frontal white matter (WM) using standard PRESS (TE = 30 ms and 270 ms) and STEAM (TE = 20 ms) MRS sequences at multiple times after birth from 5 to 60 days. A total of 74 scans met quality standards for inclusion, reflecting a spectrum of neonatal disease and several months of early infant development. For the long TE PRESS sequence, N‐acetylaspartate (NAA) and Choline (Cho) ratios to Creatine (Cr) correlated strongly between LCModel and vendor‐supplied software in the BG. For shorter TEs, the ratios of NAA/Cr and Cho/Cr were more closely related using STEAM at TE = 20 ms in BG and WM, which was significantly better than using PRESS at TE = 30 ms in the BG of HIE infants. At short TEs, however, it is still unclear which MRS sequence, STEAM or PRESS, is superior and thus more work is required in this regard for translating research‐generated MRS ratios to clinical diagnosis and prognostication, and unlocking the potential of MRS for in vivo metabolomics. MRS at both long and short TEs is desirable for standard metabolites such as NAA, Cho and Cr, along with important lower concentration metabolites such as myo‐inositol and glutathione.

Depression is a serious mental illness that is frequently resistant to a first round of pharmacotherapy. Electroconvulsive therapy (ECT) is effective even for such treatment resistant depression but is associated with significant adverse effects. Repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex in comparison causes only mild discomfort but is less effective than ECT. We hypothesize that TMS treatment efficacy could be improved by locking TMS onset to a specific, potentially subject specific phase of the prefrontal alpha rhythm in the electroencephalogram (EEG). Here, we present an instrument that can track and predict phase of the alpha rhythm in the EEG to precisely target TMS while concurrently recording functional magnetic resonance imaging (fMRI) to study local and distributed hemodynamic brain responses to stimulation. Tests of the instrument with three healthy adults indicate that EEG phase-locked TMS can be administered accurately enough to start testing systematically whether specific stimulation protocols can lead to clinically significant improvements in depression. To our knowledge, this is the first system that can deliver TMS phase-locked to the alpha rhythm while concurrently recording fMRI. For patients, such EEG guided TMS treatment could lead to better clinical outcomes and lower incidence of adverse effects.

Background Proton magnetic resonance spectroscopy (1 H-MRS) studies have demonstrated abnormal levels of a variety of neurometabolites in inpatients/outpatients with alcohol use disorder (AUD) following acute alcohol withdrawal relative to healthy controls. In contrast, few studies have compared neurometabolite levels between less severe, treatment-naive AUD individuals and light drinkers (LD) or related them to recent alcohol consumption. The present study compared neurometabolite levels between treatment-naive AUD and LD individuals. Methods Twenty treatment-naive individuals with AUD and 20 demographically matched LD completed an 1 H-MRS scan, approximately 2.5 days following their last reported drink. 1 H-MRS data were acquired in dorsal anterior cingulate (dACC) using a 2-dimensional J-resolved point-resolved spectroscopy sequence. dACC neurometabolite levels, with a focus on glutamate, glutamine, and GABA, were compared between AUD and LD participants. The associations between metabolite levels and recent drinking were explored. Results AUD participants had significantly lower concentrations of GABA (Cohen's d = 0.79, p = 0.017) and glutamine (Cohen's d = 1.12, p = 0.005), but not glutamate (Cohen's d = 0.05, p = 0.893), relative to LD. As previously reported, AUD participants' glutamate and N-acetylaspartate concentrations were inversely associated with their number of heavy drinking days. In contrast, neither number of drinking (mean p = 0.56) nor heavy drinking (mean p = 0.47) days were associated with metabolite concentrations in LD. Conclusions The present study demonstrated significantly lower levels of prefrontal γ-aminobutyric acid and glutamine in treatment-naive individuals with AUD relative to LD. Whether these findings reflect the neurotoxic consequence and/or neuroadaptive response of alcohol consumption versus a predrinking trait, and therefore a more durable neurochemical disturbance, awaits elucidation from longitudinal studies.

Therapeutic hypothermia does not improve outcomes in neonatal hypoxia ischemia (HI) complicated by perinatal infection, due to well-described, pre-existing oxidative stress and neuroinflammation that shorten the therapeutic window. For effective neuroprotection post-injury, we must first define and then target CNS metabolomic changes immediately after endotoxin-sensitized HI (LPS-HI). We hypothesized that LPS-HI would acutely deplete reduced glutathione (GSH), indicating overwhelming oxidative stress in spite of hypothermia treatment in neonatal rats. Post-natal day 7 rats were randomized to sham ligation, or severe LPS-HI (0.5 mg/kg 4 h before right carotid artery ligation, 90 min 8% O2), followed by hypothermia alone or with N-acetylcysteine (25 mg/kg) and vitamin D (1,25(OH)2D3, 0.05 μg/kg) (NVD). We quantified in vivo CNS metabolites by serial 7T MR Spectroscopy before, immediately after LPS-HI, and after treatment, along with terminal plasma drug concentrations. GSH was significantly decreased in all LPS-HI rats compared with baseline and sham controls. Two hours of hypothermia alone did not improve GSH and allowed glutamate + glutamine (GLX) to increase. Within 1 h of administration, NVD increased GSH close to baseline and suppressed GLX. The combination of NVD with hypothermia rapidly improved cellular redox status after LPS-HI, potentially inhibiting important secondary injury cascades and allowing more time for hypothermic neuroprotection.

PURPOSE This study used kinematic analysis to identify a reliable and rapid assessment method for abnormal patterns of motor development in preterm infants. METHODS In a retrospective analysis, we examined video of n= 35 preterm infants at 3mo corrected age (CA) who had concurrent Test of Infant Motor Performance (TIMP) scores. Hyperflexion at the hip produces common gait anomalies seen in children with CP, therefore we analyzed hip angle in the prone head lift position at 3 months CA. Magnetic Resonance Spectroscopy (MRS) was performed at term equivalent (n= 23) and Bayley-III neurodevelopmental tests were performed at 1 year (n= 28). We correlated hip angles with TIMP and Bayley-III scores, and MRS neuronal metabolites. RESULTS Hip angle positively correlated with TIMP at 3 months (r= 0.642, p≤ 0.001), but not with Bayley-III at 1 year (r= 0.122, p= 0.529). Hip angle correlated negatively with myo-inositol (mI) ratios in frontal white matter tracts (mI/Cr r= -0.520, p= 0.011). CONCLUSIONS These results suggest prone hip angle may be a quantitative proxy for the 42-item TIMP at 3 months, and that hypertonicity in the hip flexor musculature is a manifestation of white matter metabolic abnormalities (elevated mI ratios) that may indicate occult white matter injury.

Persistent oxidative stress depletes reduced glutathione (GSH), an intracellular antioxidant and an important determinant of CNS injury after hypoxia ischemia. We used standard, short echo time Stimulated Echo Acquisition Mode (STEAM) to detect GSH by magnetic resonance spectroscopy (MRS) in 24 term neonates with hypoxic-ischemic encephalopathy (HIE), on day of life 5–6, after rewarming from therapeutic hypothermia. MRS demonstrated reliable, consistent GSH of 1·64 ± 0·20 mM in the basal ganglia immediately before intravenous infusion of N-acetylcysteine. N-acetylcysteine resulted in a rapid and significant GSH increase to 1·93 ± 0.23 mM within 12–30 min after completion of infusion ( n = 21, p

Objective: Evaluate brain metabolites, which reflect neuroinflammation, and relate to neurodevelopmental outcomes in healthy term neonates exposed to chorioamnionitis. Study Design: Thirty-one healthy term neonates with documented fetal inflammatory response after maternal chorioamnionitis underwent magnetic resonance spectroscopy (MRS), with voxels placed in basal ganglia (BG) and frontal white matter. Bayley III examinations were performed at 12 months of age. Result: Infants with below average outcomes did not show the same increase in NAA/Cho ratios postnatally as the group with normal outcomes. Decreased NAA/Cho and increased Lac/Cr in BG correlated with lower motor and cognitive composite scores, respectively, controlling for postnatal age. In males, increased lactate/NAA in BG were associated with lower motor scores. Funisitis severity was associated with decreased NAA/Cho and increased mI/NAA in males. Conclusion: In healthy term newborns with chorioamnionitis, MRS ratios shortly after birth may provide evidence of occult neuroinflammation, which may be associated with worse performance on 1-year neurodevelopmental tests.

Background: High-resolution MRI (HRMRI) is a promising tool for studying intracranial atherosclerotic disease (ICAD) in-vivo, but its use to understand the pathophysiology of ICAD has been limited by a lack of correlation between MRI signal characteristics and pathology in intracranial arteries. Description of case: A patient with symptomatic left cavernous carotid stenosis underwent 3T HRMRI and died 4 days later. In-vivo HRMRI and postmortem histopathology images were compared. MRI signal characteristics consistent with atherosclerotic plaque composed of lipid and loose matrix, fibrous tissue, and calcium were correlated with pathology findings. Intraplaque hemorrhage was not present on HRMRI or pathology. Conclusions: This report demonstrates correlation between atherosclerotic plaque components visualized on 3T HRMRI images obtained in-vivo and pathological specimens of a symptomatic ICAD plaque, providing an important step in developing HRMRI as an in-vivo research tool to understand ICAD pathology.

Focused attention continuously and inevitably fluctuates, and to completely understand the mechanisms responsible for these modulations it is necessary to localize the brain regions involved. During a simple visual oddball task, neural responses measured by electroencephalography (EEG) modulate primarily with attention, but source localization of the correlates is a challenge. In this study we use single-trial analysis of simultaneously-acquired scalp EEG and functional magnetic resonance image (fMRI) data to investigate the blood oxygen level dependent (BOLD) correlates of modulations in task-related attention, and we unravel the temporal cascade of these transient activations. We hypothesize that activity in brain regions associated with various task-related cognitive processes modulates with attention, and that their involvements occur transiently in a specific order. We analyze the fMRI BOLD signal by first regressing out the variance linked to observed stimulus and behavioral events. We then correlate the residual variance with the trial-to-trial variation of EEG discriminating components for identical stimuli, estimated at a sequence of times during a trial. Post-stimulus and early in the trial, we find activations in right-lateralized frontal regions and lateral occipital cortex, areas that are often linked to task-dependent processes, such as attentional orienting, and decision certainty. After the behavioral response we see correlates in areas often associated with the default-mode network and introspective processing, including precuneus, angular gyri, and posterior cingulate cortex. Our results demonstrate that during simple tasks both task-dependent and default-mode networks are transiently engaged, with a distinct temporal ordering and millisecond timescale.

Background: In the 20 years since our group established the feasibility of performing interleaved TMS/fMRI, no studies have reported direct comparisons of active prefrontal stimulation with a matched sham. Thus, for all studies there is concern about what is truly the TMS effect on cortical neurons. Objective: After developing a sham control for use within the MRI scanner, we used fMRI to test the hypothesis of greater regional BOLD responses for active versus control stimulation. Methods: We delivered 4 runs of interleaved TMS/fMRI with a limited field of view (16 slices, centered at AC-PC) to the left DLPFC (2 active, 2 control; counterbalanced) of 20 healthy individuals (F3; 20 pulses/run, interpulse interval:10–15sec, TR:1sec). In the control condition, 3 cm of foam was placed between the TMS coil and the scalp. This ensured magnetic field decay, but preserved the sensory aspects of each pulse (empirically evaluated in a subset of 10 individuals). Results: BOLD increases in the cingulate, thalamus, insulae, and middle frontal gyri (p

Patients with acute uncomplicated Plasmodium falciparum malaria have no evident neurologic disorder, vital organ dysfunction, or other severe manifestations of infection. Nonetheless, parasitized erythrocytes cytoadhere to the endothelium throughout their microvasculature, especially within the brain. We aimed to determine if 3 Tesla magnetic resonance imaging studies could detect evidence of cerebral abnormalities in these patients. Within 24 hours of admission, initial magnetic resonance imaging examinations found a lesion with restricted water diffusion in the mid- portion of the splenium of the corpus callosum of 4 (40%) of 10 male patients. The four patients who had a splenial lesion initially had evidence of more severe hemolysis and thrombocytopenia than the six patients who had no apparent abnormality. Repeat studies four weeks later found no residua of the lesions and resolution of the hematologic differences. These observations provide evidence for acute cerebral injury in the absence of severe or cerebral malaria.

Purpose A novel longitudinal relaxation time (T1) measurement method using complex amplitude modulation is presented. Theory The method applies a series of inversion pulses to the imaged region in accordance with a binary modulation sequence. The longitudinal magnetization acquired in a given pulse repetition time (TR) interval is the sum of the individual longitudinal magnetization recovered during each previous TR interval, weighted by T1 decay factors and the combined effect of all the radiofrequency pulses they have experienced. The demodulated signal for each voxel is an exponential curve with a decaying rate determined by T1 and the acquisition flip angle θ. Methods Sequences using a 15-cycle pseudorandom binary code were implemented on Siemens 3T Trio with standard gradient echo readout and multislice gradient echo-planar imaging. The sequences were tested on T1 phantoms and human and compared against inversion recovery method. Results Our studies on phantoms and a human volunteer show that T1 estimated from this method is very accurate and well reproducible. The average scan time is ∼1.6 s per slice (full k-space gradient echo-planar imaging with matrix size 128 × 128). Conclusion The current protocol is almost twice as fast as two fastest existing methods. Optimizing protocols and incorporating common acceleration techniques will make it even faster. Magn Reson Med 71:2155–2165, 2014. © 2013 Wiley Periodicals, Inc.

Atherosclerosis occurs in diverse vascular beds and may result in tissue ischemia. Current understanding of atherosclerotic disease has been advanced by imaging techniques, such as HRMRI studies of the coronary and carotid arteries. In these vessels, atherosclerotic plaque components can be visualized to risk-stratify patients, select treatments, and advance our understanding of atherosclerosis pathophysiology in vivo. These imaging techniques are now being applied to evaluate intracranial arterial disease, both atherosclerotic and nonatherosclerotic. This review highlights the mechanisms by which intracranial atherosclerotic disease (ICAD) causes ischemia, the potential for HRMRI to identify intracranial arterial pathology, the limitations of HRMRI in the intracranial circulation, and future applications of HRMRI for ICAD. Image quality in MRI depends on several factors (eg, slice thickness, field of view, signal-to-noise ratio, matrix size, and magnetic field strength), but the term HRMRI is not well defined. In this review, the operational definition of HRMRI is limited to magnetic resonance acquisitions using clinically available 1.5 to 3.0 T magnetic field strengths targeted to intracranial arterial pathology that are of sufficient quality to visualize the arterial wall, separate from the lumen, of the proximal circle of Willis vessels. HRMRI can be accomplished at 1.5 T by limiting the field of view to focus on a single vessel or point of interest, but higher field strength at 3.0 T has many advantages over conventional (1.5 T) MRI. Image acquisition is faster1 and there are increased signal-to-noise2 and contrast-to-noise ratios, with better image quality3 for black-blood imaging. The increased signal and contrast that 3 T provides improves the detection of complex atherosclerotic plaque4 and can identify plaque components in larger arteries.5 Two-dimensionally acquired HRMRI is time consuming and must be monitored by a neuroradiologist to ensure adequate sampling of the lesions of interest. HRMRI using 3-dimensional …

Background Cerebral microbleeds ( CMB s) represent intracerebral hemorrhages due to amyloid angiopathy or exposure to modifiable risk factors. Few community‐based stroke‐free studies including blacks and Hispanics have been done. Methods and Results The Northern Manhattan Study ( NOMAS ) is a stroke‐free, racially and ethnically diverse cohort study. Brain MRI was performed in 1290 participants, 925 of whom had available T2* gradient‐recall echo data. We used multivariable logistic regression to examine the association of sociodemographics, vascular risk factors, apolipoprotein E ( APOE ) genotype, and brain MRI markers with CMB presence and location. The prevalence of CMB s in our cohort was 5%. Of the 46 participants with CMB s, 37% had only deep CMB s, 48% had only lobar CMB s, and 15% had CMB s in both locations. The difference in CMB distribution was not statistically significant across race/ethnic group or APOE genotype. In multivariable analyses, age ( OR [95% CI ]: 1.09 [1.04, 1.15]) and SBI s (2.58 [1.01, 6.59]) were positively associated with CMB presence, and diabetes medication use was negatively associated (0.25 [0.07, 0.86]). Conclusions CMB s may represent the severity of vascular disease in this racially and ethnically diverse cohort. Larger studies are needed to elucidate the association between diabetes medication use and CMB presence.

BACKGROUND AND PURPOSE: While there have been recent reports of brain retention of gadolinium following gadolinium-based contrast agent administration in adults, a retrospective series of pediatric patients has not previously been reported, to our knowledge. We investigated the relationship between the number of prior gadolinium-based contrast agent doses and increasing T1 signal in the dentate nucleus on unenhanced T1-weighted MR imaging. We hypothesized that despite differences in pediatric physiology and the smaller gadolinium-based contrast agent doses that pediatric patients are typically administered based on weighted-adjusted dosing, the pediatric brain would also demonstrate dose-dependent increasing T1 signal in the dentate nucleus. MATERIALS AND METHODS: We included children with multiple gadolinium-based contrast agent administrations at our institution. A blinded reader placed ROIs within the dentate nucleus and adjacent cerebellar white matter. To eliminate reader bias, we also performed automated ROI delineation of the dentate nucleus, cerebellar white matter, and pons. Dentate-to-cerebellar white matter and dentate-to pons ratios were compared with the number of gadolinium-based contrast agent administrations. RESULTS: During 20 years at our institution, 280 patients received at least 5 gadolinium-based contrast agent doses, with 1 patient receiving 38 doses. Sixteen patients met the inclusion/exclusion criteria for ROI analysis. Blinded reader dentate-to-cerebellar white matter ratios were significantly associated with gadolinium-based contrast agent doses (rs = 0.77, P = .001). The dentate-to-pons ratio and dentate-to-cerebellar white matter ratios based on automated ROI placement were also significantly correlated with gadolinium-based contrast agent doses (t = 4.98, P CONCLUSIONS: In pediatric patients, the number of prior gadolinium-based contrast agent doses is significantly correlated with progressive T1-weighted dentate hyperintensity. Definitive confirmation of gadolinium deposition requires tissue analysis. Any potential clinical sequelae of gadolinium retention in the developing brain are unknown. Given this uncertainty, we suggest taking a cautious stance, including the use, in pediatric patients, of higher stability, macrocyclic agents, which in both human and animal studies have been shown to be associated with lower levels of gadolinium deposition, and detailed documentation of dosing. Most important, a patient should not be deprived of a well-indicated contrasted MR examination.

Perceptual decisions depend on coordinated patterns of neural activity cascading across the brain, running in time from stimulus to response and in space from primary sensory regions to the frontal lobe. Measuring this cascade and how it flows through the brain is key to developing an understanding of how our brains function. However observing, let alone understanding, this cascade, particularly in humans, is challenging. Here, we report a significant methodological advance allowing this observation in humans at unprecedented spatiotemporal resolution. We use a novel encoding model to link simultaneously measured electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) signals to infer the high-resolution spatiotemporal brain dynamics taking place during rapid visual perceptual decision-making. After demonstrating the methodology replicates past results, we show that it uncovers a previously unobserved sequential reactivation of a substantial fraction of the pre-response network whose magnitude correlates with decision confidence. Our results illustrate that a temporally coordinated and spatially distributed neural cascade underlies perceptual decision-making, with our methodology illuminating complex brain dynamics that would otherwise be unobservable using conventional fMRI or EEG separately. We expect this methodology to be useful in observing brain dynamics in a wide range of other mental processes.

Despite rigid-body realignment to compensate for head motion during an echo-planar imaging time-series scan, nonrigid image deformations remain due to changes in the effective shim within the brain as the head moves through the B0 field. The current work presents a combined prospective/retrospective solution to reduce both rigid and nonrigid components of this motion-related image misalignment. Prospective rigid-body correction, where the scan-plane orientation is dynamically updated to track with the subject's head, is performed using an active marker setup. Retrospective distortion correction is then applied to unwarp the remaining nonrigid image deformations caused by motion-induced field changes. Distortion correction relative to a reference time-frame does not require any additional field mapping scans or models, but rather uses the phase information from the echo-planar imaging time-series itself. This combined method is applied to compensate echo-planar imaging scans of volunteers performing in-plane and through-plane head motions, resulting in increased image stability beyond what either prospective or retrospective rigid-body correction alone can achieve. The combined method is also assessed in a blood oxygen level dependent functional MRI task, resulting in improved Z-score statistics. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.

Patient motion during an MRI exam can result in major degradation of image quality, and is of increasing concern due to the aging population and its associated diseases. This work presents a general strategy for real-time, intraimage compensation of rigid-body motion that is compatible with multiple imaging sequences. Image quality improvements are established for structural brain MRI acquired during volunteer motion. A headband integrated with three active markers is secured to the forehead. Prospective correction is achieved by interleaving a rapid track-and-update module into the imaging sequence. For every repetition of this module, a short tracking pulse-sequence remeasures the marker positions; during head motion, the rigid-body transformation that realigns the markers to their initial positions is fed back to adaptively update the image-plane—maintaining it at a fixed orientation relative to the head—before the next imaging segment of k-space is acquired. In cases of extreme motion, corrupted lines of k-space are rejected and reacquired with the updated geometry. High-precision tracking measurements (0.01 mm) and corrections are accomplished in a temporal resolution (37 ms) suitable for real-time application. The correction package requires minimal additional hardware and is fully integrated into the standard user interface, promoting transferability to clinical practice. Magn Reson Med, 2009. © 2009 Wiley-Liss, Inc.

The purpose of this preliminary study was to examine cerebral blood flow (CBF) as measured by arterial spin labeling (ASL) in tissue classified as white matter hyperintensities (WMH), normal appearing white matter, and grey matter. Seventeen healthy older adults received structural and ASL MRI. Cerebral blood flow was derived for three tissue types: WMH, normal appearing white matter, and grey matter. Cerebral blood flow was lower in WMH areas relative to normal appearing white matter, which in turn, was lower than grey matter. Regions with consistently lower CBF across individuals were more likely to appear as WMH. Results are consistent with an emerging literature linking diminished regional perfusion with the risk of developing WMH.

Background and Purpose— We examined white matter hyperintensity volume (WMHV) and subclinical infarction (no history of clinical stroke; SI) in relation to performance on tests of sequencing, cognitive flexibility, and sensorimotor ability. Methods— The Northern Manhattan Study includes a stroke-free community-based sample of Hispanic, Black, and White participants. A subsample (n=656) has undergone measurement of WMHV, SI, and neuropsychological testing. Linear regression was used to examine WMHV and SI in relation to performance on tests of sequencing as measured by Color Trails 1, cognitive flexibility as measured by Color Trails 2, and sensorimotor ability as measured by Grooved Pegboard, using generalized estimating equations (GEE) to account for the correlation among the cognitive tests and other covariates. Results— Considering performance on the tests of sequencing, cognitive flexibility, and sensorimotor ability simultaneously using GEE, WMHV and subclinical infarction were each associated with worse cognitive performance globally. There was a threshold effect for WMHV with those in the upper quartile performing significantly worse on the tests of cognitive flexibility and sensorimotor ability. Those with frontal SI performed worse on the test of cognitive flexibility and those with deep SI, worse on the test of sequencing. Conclusions— Both SI and WMHV were associated with globally worse cognitive performance. Participants with WMH affecting more than 0.75% of cranial volume had significantly slower performance on a task of cognitive flexibility and sensorimotor ability than those in the lowest quartile. The effects of SI on cognitive performance varied by location.

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.

Risk factors for subclinical brain infarcts (SBI) have not been well studied, especially in Hispanic and black populations who may be at higher risk for vascular disease. We examined the prevalence and determinants of SBI in a multiethnic community cohort.The Northern Manhattan Study (NOMAS) includes 892 stroke-free participants who underwent brain MRI. Baseline demographic and vascular risk factor data were collected. The presence of SBI was determined from the size, location, and imaging characteristics of the lesion based on fluid attenuated inversion recovery (FLAIR) T1 and T2, and proton density MRI sequences. We calculated the prevalence of SBI and cross-sectional associations with sociodemographic and vascular risk factors, using logistic regression to adjust for relevant covariates.Among 892 subjects (mean age 71.3 years), 158 (17.7%) had SBI (13.5% had 1 lesion, 4.3% had1 lesion). Of the total 216 infarcts, most were small (1 cm, 82.4%) and subcortical (82.9%). SBI prevalence increased with age (65: 9.7%; 65 to 75: 16.4%;75: 26.1%), was increased among men (21.3% vs 15.2% in women), and was increased among blacks (24.0% vs 18.1% in whites and 15.8% in Hispanics). The presence of SBI was independently associated with older age (per year: OR 1.06, 95% CI 1.04 to 1.09), male sex (OR 1.79, 95% CI 1.22 to 2.61), and hypertension (OR 2.08, 95% CI 1.35 to 3.22) adjusting for age, sex, race-ethnicity, and vascular risk factors. A significant interaction (p = 0.002) between race and age was observed such that younger black subjects had greater odds of having SBI.SBI were detected in nearly 18% of subjects in a multiethnic community-based cohort. Age, male sex, and hypertension were independently associated with SBI. Subclinical cerebral infarcts are more prevalent than symptomatic infarcts and may increase the true public health burden of stroke.

Recent neuroimaging studies have converged to show that odorant-induced responses to prolonged stimulation in primary olfactory cortex (POC) are characterized by a rapidly habituating time course. Different statistical approaches have effectively modeled this time course. One approach explicitly modeled rapid habituation using an exponentially decaying reference waveform that decreased to baseline levels within 30 to 40 s. A second approach modeled an early transient response by simply shortening the odorant 'ON' period to be less than the actual stimulation period (i.e., 9 of 40 s). The goal of the current study was to validate, compare, and optimize these methodological approaches by applying them to an olfactory fMRI block-design dataset from 10 healthy young subjects presented with odorants for 12 s (ON), alternating with 30 s of clear air (OFF). Both approaches significantly improved sensitivity to odorant-induced signal changes in POC relative to a square-wave model based on the actual stimulation period. Our findings further demonstrate that the 'optimal' model fit to the data was achieved by shortening the odorant 'ON' period to approximately 6 s. These results suggest that sensitivity to odorant-induced POC activity in block-design experiments can be optimized by modeling an early phasic response followed by a precipitous rather than specific exponential decrease to baseline levels. Notably, whole brain voxel-wise analyses further established that modeling rapid habituation in this way is not only sensitive, but also highly specific to odorant-induced activation in a well-established network of olfactory-related brain areas.

Background Intracranial atherosclerosis is a leading cause of stroke, but little is known about the composition of the intracranial atherosclerotic lesion and how intracranial plaque morphology is related to the risk of stroke. High-resolution magnetic resonance imaging (HR MRI) has been used in patients with extracranial carotid atherosclerosis as an in vivo tool to identify, with high-interrater agreement, histologically defined plaque components (i.e., intraplaque hemorrhage, fibrous cap, and lipid core), which have been shown to be predictors of recurrent stroke. With careful imaging the components of atherosclerotic plaque can be visualized in the intracranial arteries using HR MRI, but there are no reports of reproducibility or interrater reliability. Methods/Study design The Characterization of intracranial atherosclerotic stenosis using high-resolution MRI (CHIASM) study is a single-center NIH-funded prospective observational study, to (1) demonstrate high -interrater agreement for identifying intracranial plaque components on HR MRI, (2) determine the frequency of these components in symptomatic versus asymptomatic plaques, and (3) estimate the 1-year rate of stroke in the territory of high-risk plaque components. CHIASM will recruit 90 patients with 50–99% intracranial atherosclerosis to undergo HRMRI of the intracranial artery plaque at enrollment and 1-year follow-up. Both symptomatic and asymptomatic subjects will be recruited. Conclusion Determination of good interrater reliability is an important first step in the development of HR MRI as a tool to predict risk in patients with intracranial atherosclerosis. This study will inform the design of future multicenter studies to determine the prevalence and prognosis of intracranial atherosclerotic plaque components. Such studies could lead to new understanding of the pathophysiological mechanisms of cerebral ischemia in patients with atherosclerotic intracranial stenosis, improvements in risk stratification, and potentially to new treatments of this common and serious disease.

Objective—To evaluate effects of 2 commercially available colostrum replacement products on serum IgG and total protein concentrations in dairy calves. Design—Prospective clinical trial. Animals—84 Holstein bull calves from a single dairy. Procedures—Calves were randomly assigned to be given 4 quarts of colostrum (group 1; n = 21), 2 packages of a colostrum replacement product (product A; group 2; 21), 1 package of a different colostrum replacement product (product B; group 3; 21), or 2 packages of product B (group 4; 21). Treatments were given within 3 hours after birth, and blood samples were collected 24 hours later and submitted for determination of serum total protein and IgG concentrations. Results—Group 1 calves had significantly higher serum total protein and IgG concentrations than did calves in the other 3 groups. However, the percentage of calves with adequate passive transfer (ie, serum IgG concentration > 1,000 mg/dL) was not significantly different among groups 1 (90%), 3 (81%), and 4 (95%). In contrast, only 10% of calves in group 2 had adequate passive transfer. It was predicted that calves fed product B that had serum total protein concentrations > 5.2 g/dL would have serum IgG concentrations > 1,000 mg/dL at least 90% of the time. Conclusions and Clinical Relevance—Results indicated that product B could be considered as an alternative to colostrum in dairy calves, but product A failed to routinely provide adequate serum IgG concentrations when fed according to label directions.

MRI estimations of cerebral blood volume (CBV), useful in mapping brain dysfunction, typically require intravenous (IV) injections of contrast agents. Transgenically engineered mice have emerged as the dominant animal model with which to investigate disorders of the brain and novel therapeutic agents. The difficulty in gaining IV access in mice prohibits repeated administration of contrast in the same animal, limiting the ability to map CBV changes over time. Here we address this limitation by first optimizing an approach for estimating CBV that relies on intraperitoneal (IP) rather than IV injections of the contrast agent gadodiamide. Next, we show that CBV maps generated with IP or IV injections are quantitatively comparable. Finally, we show that CBV maps generated with IP gadodiamide can be acquired repeatedly, reliably and safely over time. Although this approach has certain limitations, estimating CBV with IP injections is well-suited for mapping the spatiotemporal pattern of brain dysfunction in mice models of disease, and for testing pharmacological agents.

Contains fulltext : 51298.pdf (Publisher’s version ) (Closed access) The standardization and reproducibility of techniques required to acquire anatomically localized 31P MR spectra non-invasively while studying tumors in cancer patients in a multi-institutional group at 1.5 T are reported. This initial group of patients was studied from 1995 to 2000 to test the feasibility of acquiring in vivo localized 31P MRS in clinical MR spectrometers. The cancers tested were non-Hodgkin's lymphomas, sarcomas of soft tissue and bone, breast carcinomas and head and neck carcinomas. The best accrual and spectral quality were achieved with the non-Hodgkin's lymphomas. The initial analysis of the spectral values of the sum of phosphoethanolamine plus phosphocholine normalized by the content of nucleotide triphosphates in a homogeneous sample of 32 NHL patients studied by in vivo (31)P MRS showed good reproducibility among different institutions. No statistical differences were found between the institution with the largest number of cases accrued and the rest of the multi-institutional NHL data (2.28 +/- 0.64, mean +/- standard error; n = 17, vs 2.08 +/- 0.14, n = 15). The preliminary data reported demonstrate that the institutions involved in this trial are obtaining reproducible 31P MR spectroscopic data non-invasively from human tumors. This is a fundamental prerequisite for the international cooperative group to be able to demonstrate the clinical value of the normalized determination of phosphoethanolamine plus phosphocholine by 31P MRS as predictor for treatment response in cancer patients.

EEG alpha-band activity is generally thought to represent an inhibitory state related to decreased attention and play a role in suppression of task-irrelevant stimulus processing, but a competing hypothesis suggests an active role in processing task-relevant information - one in which phase dynamics are involved. Here we used simultaneous EEG-fMRI and a whole-brain analysis to investigate the effects of prestimulus alpha activity on the event-related BOLD response during an auditory oddball task. We separately investigated the effects of the posterior alpha rhythm's power and phase on activity related to task-relevant stimulus processing and also investigated higher-level decision-related processing. We found stronger decision-related BOLD activity in areas late in the processing stream when subjects were in the high alpha power state prior to stimulus onset, but did not detect any effect in primary sensory regions. Our phase analysis revealed correlates in the bilateral thalamus, providing support for a thalamo-cortical loop in attentional modulations and suggesting that the cortical alpha rhythm acts as a cyclic modulator of task-related responses very early in the processing stream. Our results help to reconcile the competing inhibition and active-processing hypotheses for ongoing alpha oscillations and begin to tease apart the distinct roles and mechanisms underlying their power and phase.

T1 relaxographic imaging is a precise and accurate way to characterize tissue. A number of fast MRI acquisition techniques allow both spatial and magnetization recoveries to be well sampled in reasonable imaging times. However, two limitations common to the analysis of relaxographic imaging data are (1) the assumption of single exponential behavior for each image voxel and (2) the treatment of each pixel as an independent entity. The first assumption disregards tissue heterogeneity known to be present and reduces the information content that can be extracted. The latter assumption reduces both the modeling stability and the accuracy of extracted parameters. A new method that overcomes these limitations is presented here. The method, Bayesian Image Decomposition, recovers individual tissue type magnetization recovery curves and their corresponding tissue-specific relaxographic images (i.e. segmented images) from a series of inversion recovery images. The general form of the decomposition is given together with its specific implementation to longitudinal relaxographic imaging. The method is validated by comparison of the results with those of the standard method and by comparison across data sets. A specific advantage of the new method is the ability to determine fractional contributions of tissue subtypes to each image voxel. © 2005 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 15;2–9, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/ima.20033

Rationale and objectives Phosphoethanolamine and phosphocholine, shown to be elevated in tumors and possibly related to apoptotic signaling, have the potential to be prognostic variables of cancer treatment. Materials and methods The sum of phosphoethanolamine and phosphocholine normalized by nucleotide-triphosphates was determined in tumors of non-Hodgkin’s lymphoma (NHL) patients via in vivo 31 P MR spectroscopy. Results The normalized sum of phosphoethanolamine and phosphocholine showed significant differences in tumors of patients who had a complete response to treatment against those who did not ( t -test: 1.45 ± 0.15, mean ± standard error, n = 10 vs. 2.28 ± 0.15, n = 17, P P P P P Conclusion The normalized sum of phosphoethanolamine and phosphocholine measured before treatment successfully predicts long-term response to treatment and time to treatment failure in non-Hodgkin’s lymphoma, particularly when combined with the IPI.

Motivation: Detailed comparison and analysis of the output of DNA gene expression arrays from multiple samples require global normalization of the measured individual gene intensities from the different hybridizations. This is needed for accounting for variations in array preparation and sample hybridization conditions. Results: Here, we present a simple, robust and accurate procedure for the global normalization of datasets generated with single-channel DNA arrays based on principal component analysis. The procedure makes minimal assumptions about the data and performs well in cases where other standard procedures produced biased estimates. It is also insensitive to data transformation, filtering (thresholding) and pre-screening.

Contains fulltext : 142496.pdf (Publisher’s version ) (Closed access) RATIONALE AND OBJECTIVES: Combinations of chemotherapy and fractionated radiation therapy are the currently preferred nonsurgical treatment methods for squamous cell carcinoma of the head and neck, but to the authors' knowledge there is no reliable marker for predicting therapeutic response. Early identification of nonresponders would allow prompt replacement of ineffective, toxic therapy by alternative, potentially more effective procedures. Frequent regional node involvement facilitates surface coil investigation with phosphorus-31 magnetic resonance spectroscopy. MATERIALS AND METHODS: P-31 magnetic resonance spectra were acquired from 12 patients before radiation therapy or chemotherapy. In vivo three-dimensional localized P-31 nuclear magnetic resonance chemical shift imaging was performed with a 1.5-T clinical imager and a dual-tuned H-1/P-31 surface coil. Proton decoupling and nuclear Overhauser enhancement were used to improve sensitivity and resolve overlapping signals in the phosphomonoester region of the spectrum. RESULTS: The average pretreatment ratio of phosphomonoester to beta-nucleoside triphosphate was significantly smaller in complete responders (n = 4) than in incomplete responders (partial responders plus nonresponders, n = 8) (0.0 +/- 0.0 vs 1.22 +/- 0.17 [P = .004]). CONCLUSION: Results of this preliminary study suggest that H-1-decoupled P-31 magnetic resonance spectroscopy may prove to be a useful predictor of therapeutic response in head and neck cancers.

Contains fulltext : 140536.pdf (Publisher’s version ) (Closed access) Based on their association with malignant proliferation, using noninvasive phosphorus MR spectroscopic imaging ((31)P MRSI), we measured the tumor content of the phospholipid-related phosphomonoesters (PME), phosphoethanolamine and phospholcholine, and its correlation with treatment outcome in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) receiving standard first-line chemotherapy.The PME value normalized to nucleoside triphosphates (PME/NTP) was measured using (31)P MRSI in tumor masses of 20 patients with DLBCL before receiving standard first-line chemotherapy. Response at 6 months was complete in 13 patients and partial in seven. Time to treatment failure (TTF) was ≤11 months in eight patients, from 18 to 30 months in three, and ≥60 months in nine.On a t test, the pretreatment tumor PME/NTP mean value (SD, n) of patients with a complete response at 6 months was 1.42 (0.41, 13), which was significantly different from the value of 2.46 (0.40, 7) in patients with partial response (P < .00001). A Fisher test significantly correlated the PME/NTP values with response at 6 months (sensitivity and specificity at 0.85, P < .004) while a Cox proportional hazards regression significantly correlated the PME/NTP values with TTF (hazard ratio = 5.21, P < .02). A Kaplan-Meier test set apart a group entirely composed of patients with TTF ≤ 11 months (hazard ratio = 8.66, P < .00001).The pretreatment tumor PME/NTP values correlated with response to treatment at 6 months and time to treatment failure in newly diagnosed patients with DLBCL treated with first-line chemotherapy, and therefore they could be used to predict treatment outcome in these patients.

✓ The authors represent a cooperative group of 15 institutions that examined the feasibility of using metabolic features observed in vivo with 1H-magnetic resonance (MR) spectroscopy to characterize brain tumors of the glial type. The institutions provided blinded, centralized MR spectroscopy data processing along with independent central review of MR spectroscopy voxel placement, composition and contamination by brain, histopathological typing using current World Health Organization criteria, and clinical data. Proton 1H-MR spectroscopy was performed using a spin-echo technique to obtain spectra from 8-cc voxels in the tumor and when feasible in the contralateral brain. Eighty-six cases were assessable, 41 of which had contralateral brain spectra. Glial tumors had significantly elevated intensities of choline signals, decreased intensities of creatine signals, and decreased intensities of N-acetylaspartate compared to brain. Choline signal intensities were highest in astrocytomas and anaplastic astrocytomas, and creatine signal intensities were lowest in glioblastomas. However, whether expressed relative to brain or as intratumoral ratios, these metabolic characteristics exhibited large variations within each subtype of glial tumor. The resulting overlaps precluded diagnostic accuracy in the distinction of low- and high-grade tumors. Although the extent of contamination of the 1HMR spectroscopy voxel by brain had a marked effect on metabolite concentrations and ratios, selection of cases with minimal contamination did not reduce these overlaps. Thus, each type and grade of tumor is a metabolically heterogeneous group. Lactate occurred infrequently and in all grades. Mobile lipids, on the other hand, occurred in 41% of high-grade tumors with higher mean amounts found in glioblastomas. This result, coupled with the recent demonstration that intratumoral mobile lipids correlate with microscopic tumor cell necrosis, leads to the hypothesis that mobile lipids observed in vivo in 1H-MR spectroscopy may correlate independently with prognosis of individual patients.

Antenatal surveillance is inefficient for accurately detecting fetal compromise. A noninvasive technique for assessing fetal metabolic status would be useful for clinical management.Fetal magnetic resonance spectroscopy was performed at 20 weeks in a pregnancy complicated by severe intrauterine growth restriction to determine if lactate, a metabolite associated with fetal hypoxia, was present. Two-dimensional, single-slice proton magnetic resonance spectroscopy was carried out at 1.5 T using a volume-selective, double-spin echo technique. Lactate was detected in fetal back muscle. Fetal death occurred the next day.Although this initial report is purely experimental, further development of this technique may prove to be a valuable noninvasive tool in the management of suspected fetal hypoxia.

The goal was to present and discuss recent results by MRS, which advanced basic understanding of physiology and biochemistry. The format included thirty 20-min invited talks divided into nine sessions. One third of each session was reserved for discussion, which included a stimulating short summary of the lectures by the chairman. Discussion was animated and focused. The format worked well-meeting with general approval from the 130 participants. Each chairperson wrote a short summary of the session, which is integrated here into a final report.

The importance and the difficulty of achieving good B 0 homogeneity over the volume of interest in in vivo NMR spectroscopy are well known A fast, reliable, versatile, and fully automatic shimming procedure has been developed, using 3D chemical-shift imaging to measure the field distribution using only the water peak in the sample of interest, The procedure minimizes the mean-square error in the field distribution with respect to a constant held where the signal exists (e,g., the head). This produces a set of linear equations that can be solved by standard matrix methods. The procedure has been applied on a commercial imager producing water linewidths from the entire head as low as 8 Hz at 1.5 T. The mean linewidth and standard deviation from 94 head studies were 11.7 ± 1.9 Hz.

Objective To evaluate the clinical safety of antenatal and postnatal N-acetylcysteine (NAC) as a neuroprotective agent in maternal chorioamnionitis in a randomized, controlled, double-blinded trial. Study design Twenty-two mothers >24 weeks gestation presenting within 4 hours of diagnosis of clinical chorioamnionitis were randomized with their 24 infants to NAC or saline treatment. Antenatal NAC (100 mg/kg/dose) or saline was given intravenously every 6 hours until delivery. Postnatally, NAC (12.5-25 mg/kg/dose, n = 12) or saline (n = 12) was given every 12 hours for 5 doses. Doppler studies of fetal umbilical and fetal and infant cerebral blood flow, cranial ultrasounds, echocardiograms, cerebral oxygenation, electroencephalograms, and serum cytokines were evaluated before and after treatment, and 12, 24, and 48 hours after birth. Magnetic resonance spectroscopy and diffusion imaging were performed at term age equivalent. Development was followed for cerebral palsy or autism to 4 years of age. Results Cardiovascular measures, cerebral blood flow velocity and vascular resistance, and cerebral oxygenation did not differ between treatment groups. Cerebrovascular coupling was disrupted in infants with chorioamnionitis treated with saline but preserved in infants treated with NAC, suggesting improved vascular regulation in the presence of neuroinflammation. Infants treated with NAC had higher serum anti-inflammatory interleukin-1 receptor antagonist and lower proinflammatory vascular endothelial growth factor over time vs controls. No adverse events related to NAC administration were noted. Conclusions In this cohort of newborns exposed to chorioamnionitis, antenatal and postnatal NAC was safe, preserved cerebrovascular regulation, and increased an anti-inflammatory neuroprotective protein. Trial registration ClinicalTrials.gov : NCT00724594 .