Objectives Research suggests that the majority of mild traumatic brain injury (mTBI) patients exhibit both cognitive and emotional dysfunction within the first weeks of injury, followed by symptom resolution 3–6 months post-injury. The neuronal correlates of said dysfunction are difficult to detect with standard clinical neuroimaging, complicating differential diagnosis and early identification of patients who may not recover. The current study examined whether resting state functional magnetic resonance imaging (FMRI) provides objective markers of injury and predicts cognitive, emotional and somatic complaints in mTBI patients semi-acutely (< 3 weeks post-injury) and in late recovery (3–5 month) phases. Methods Twenty seven semi-acute mTBI patients and 26 gender, age and education matched controls were studied. Fifteen out of 27 patients returned for a follow-up visit 3–5 months post-injury. The main dependent variables were spontaneous fluctuations (temporal correlation) in the default-mode (DMN) and fronto-parietal task-related (TRN) networks as measured by FMRI. Results Significant differences in self-reported cognitive, emotional and somatic complaints were observed (all p < .05), despite normal clinical (T1 and T2) imaging and neuropsychological testing results. Mild TBI patients demonstrated decreased functional connectivity within the DMN and hyper-connectivity between the DMN and lateral prefrontal cortex. Measures of functional connectivity exhibited high levels of sensitivity and specificity for patient classification and predicted cognitive complaints in the semi-acute injury stage. However, no changes in functional connectivity were observed across a four month recovery period. Conclusions Abnormal connectivity between the DMN and frontal cortex may provide objective biomarkers of mTBI and underlie cognitive impairment.

A strategy for using tissue water as a concentration standard in 1 H magnetic resonance spectroscopic imaging studies on the brain is presented, and the potential errors that may arise when the method is used are examined. The sensitivity of the method to errors in estimates of the different water compartment relaxation times is shown to be small at short echo times (TEs). Using data from healthy human subjects, it is shown that different image segmentation approaches that are commonly used to account for partial volume effects (SPM2, FSL's FAST, and K-means) lead to different estimates of metabolite levels, particularly in gray matter (GM), owing primarily to variability in the estimates of the cerebrospinal fluid (CSF) fraction. While consistency does not necessarily validate a method, a multispectral segmentation approach using FAST yielded the lowest intersubject variability in the estimates of GM metabolites. The mean GM and white matter (WM) levels of N-acetyl groups (NAc, primarily N-acetylaspartate), choline (Ch), and creatine (Cr) obtained in these subjects using the described method with The unsuppressed "internal" water signal was introduced as a concentration reference for single-voxel proton magnetic resonance spectroscopy ( 1 H-MRS) of the brain over a decade ago (1-4). However, to our knowledge, a detailed description of how this method could be applied to spectroscopic imaging (SI), or an examination of its potential sources of error has yet to be reported. In the majority of SI studies that reported "absolute" metabolite concentrations, the metabolite signals were converted to moles per liter or kilograms of tissue using either external metabolite solutions (5-7) or ventricle water (8,9), and relatively few groups have reported using internal water (10,11). The principal advantage of using internal water in SI studies is that certain factors and potential sources of error that need to be considered when using external concentration references (e.g., RF homogeneity, coil loading, or the SI point spread function (PSF)) are obviated, since the water and metabolite signals come from the same voxel and are acquired in essentially the same way.The major assumptions when using internal water, on the other hand, are that the water densities and signal relaxation times of gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) in the region of interest (ROI) can be reliably estimated and, furthermore, do not change significantly among the studied groups. Moreover, it is essential that the volume fractions of these tissues and CSF in each SI voxel are accurately measured. Measuring partial volume effects is also a requirement when using external referencing methods, but the demand on accuracy is greater when using internal water. This is because only the signal from the combined GM-WM fraction of the total water, in which the detectable metabolites are exclusively located, is used as the concentration reference. The observed water signal, however, arises from a combination of the GM, WM, and CS...

Objectives: Only a handful of studies have investigated the nature, functional significance, and course of white matter abnormalities associated with mild traumatic brain injury (mTBI) during the semi-acute stage of injury. The present study used diffusion tensor imaging (DTI) to investigate white matter integrity and compared the accuracy of traditional anatomic scans, neuropsychological testing, and DTI for objectively classifying mTBI patients from controls. Methods:Twenty-two patients with semi-acute mTBI (mean ϭ 12 days postinjury), 21 matched healthy controls, and a larger sample (n ϭ 32) of healthy controls were studied with an extensive imaging and clinical battery. A subset of participants was examined longitudinally 3-5 months after their initial visit.Results: mTBI patients did not differ from controls on clinical imaging scans or neuropsychological performance, although effect sizes were consistent with literature values. In contrast, mTBI patients demonstrated significantly greater fractional anisotropy as a result of reduced radial diffusivity in the corpus callosum and several left hemisphere tracts. DTI measures were more accurate than traditional clinical measures in classifying patients from controls. Longitudinal data provided preliminary evidence of partial normalization of DTI values in several white matter tracts.Conclusions: Current findings of white matter abnormalities suggest that cytotoxic edema may be present during the semi-acute phase of mild traumatic brain injury (mTBI). Initial mechanical damage to axons disrupts ionic homeostasis and the ratio of intracellular and extracellular water, primarily affecting diffusion perpendicular to axons. Diffusion tensor imaging measurement may have utility for objectively classifying mTBI, and may serve as a potential biomarker of recovery. Neurology® 2010;74:643-650 GLOSSARY ADC ϭ apparent diffusion coefficient; CC ϭ corpus callosum; CCI ϭ cortical impact injury model; CR ϭ corona radiata; DTI ϭ diffusion tensor imaging; EC ϭ external capsule; FA ϭ fractional anisotropy; FPI ϭ fluid percussion injury model; HC ϭ healthy controls; IC ϭ internal capsule; JHU ϭ Johns Hopkins University; MANCOVA ϭ multivariate analysis of covariance; mTBI ϭ mild traumatic brain injury; RD ϭ radial diffusivity; ROI ϭ region of interest; SCR ϭ superior corona radiata; SLF ϭ superior longitudinal fasciculus; UF ϭ uncinate fasciculus.Complex cognitive processes such as attention, executive functions, and memory depend on intact white matter tracts among frontal, parietal, and medial temporal lobes, 1 which are likely disrupted following mild traumatic brain injury (mTBI). Histologic evidence of white matter changes have been observed in both human autopsy 2,3 and animal 4 studies of mTBI. Although traditional neuroimaging sequences (i.e., T1-and T2-weighted imaging) are typically insensitive to these putative white matter changes, diffusion tensor imaging (DTI) is capable of measuring white matter pathology with histologic correlates in animal models of injury...

Once an MRS dataset has been acquired, several important steps must be taken to obtain the desired metabolite concentration measures. First, the data must be preprocessed to prepare them for analysis. Next, the intensity of the metabolite signal(s) of interest must be estimated. Finally, the measured metabolite signal intensities must be converted into scaled concentration units employing a quantitative reference signal to allow meaningful interpretation. In this paper, we review these three main steps in the post-acquisition workflow of a single-voxel MRS experiment (preprocessing, analysis and quantification) and provide recommendations for best practices at each step. Abbreviations: 1 H, proton; 13 C, carbon-13; B 0 , main magnetic field; B 1 , RF field; Cr, creatine; CRMVB, Cramér-Rao minimum variance bound; CSF, cerebrospinal fluid; d GM , water density of grey matter; d WM , water density of white matter; ERETIC, Electric Reference to Access in vivo Concentrations; f CSF , volume fraction of cerebrospinal fluid inside the MRS voxel; fCSF H2O , water mole fraction in cerebrospinal fluid; fGM, volume fraction of gray matter inside the MRS voxel; fGM H2O , water mole fraction in gray matter; FFT, fast Fourier transform; FID, free induction decay; FQN, fit quality number; FWHM, full width at half maximum; f WM , volume fraction of white matter inside the MRS voxel; fWM H2O , water mole fraction in white matter; GM, grey matter; GPC, glycerophosphocholine; [H 2 O] molal , water concentration in moles of water per kilogram of tissue water = 55.49 moles/kg; [H 2 O] molar , water concentration in moles of water per liter of tissue water; HERMES, Hadamard encoding and reconstruction of MEGA-edited spectroscopy; MEGA-PRESS, Mescher-Garwood point resolved spectroscopy; [M] GM /[M] WM , assumed ratio of grey matter to white matter metabolite concentrations; MM, macromolecules; [M]molal, metabolite concentration in moles of metabolite per kilogram of tissue water; [M]molar, metabolite concentration in moles of metabolite per liter of tissue water; MRSI, magnetic resonance spectroscopic imaging; NAA, N-acetylaspartate; NAAG, N-acetylaspartylglutamate; N M , number of protons contributing to metabolite signal; N P , number of points in FID/spectrum; N pc , number of phase encoding steps in one phase cycle; N RF , number of RF channels; N tra , number of transients;PCh, phosphocholine; PCr, phosphocreatine; RH2O CSF , relaxation scaling factor for water in cerebrospinal fluid; RH2O GM , relaxation scaling factor for water in grey matter; RH2O WM , relaxation scaling factor for water in white matter; RM, relaxation scaling factor for tissue metabolite signal; RM GM , relaxation scaling factor for metabolite in grey matter; RM WM , relaxation scaling factor for metabolite in white matter; S H2O , water signal intensity; SH2O obs , observed water signal intensity in the presence of relaxation; S M , metabolite signal intensity; SM obs , observed metabolite signal intensity in the presence of relaxation; SNR, signal-to-noise r...

Background and Purose Disruption of the blood-brain barrier (BBB) has been proposed to be important in vascular cognitive impairment (VCI). Increased cerebrospinal fluid (CSF) albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the BBB permeability in patients with VCI is lacking. Therefore, we acquired dynamic contrast-enhanced MRI (DCEMRI) to quantify BBB permeability in VCI. Method We studied 60 patients with suspected VCI. They had neurological and neuropsychological testing, permeability measurements with DCEMRI and lumbar puncture to measure albumin index (Qalb). Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts (MI/LAC), and leukoaraiosis (LA). Twenty volunteers were controls for the DCEMRI studies, and control CSF was obtained from 20 individuals undergoing spinal anesthesia for non-neurological problems. Results Thirty-six patients were classified as SIVD, 8 as MI/LAC and 9 as LA. The Qalb was significantly increased in the SIVD group compared to 20 controls. Permeabilities for the VCI patients measured by DCEMRI were significantly increased over controls (p<0.05). Patient age correlated with neither the BBB permeability nor Qalb. Highest Qalb values were seen in SIVD group (p<0.05), and were significantly increased over MI/LAC. Ki values were elevated over controls in SIVD, but were similar to MI/LAC. Conclusions There was abnormal permeability in white matter in patients with SIVD as shown by DCEMRI and Qalb. Future studies will be needed to determine the relationship of BBB damage and development of WMHs.

In this multicenter study, 2D spatial mapping of J-coupled resonances at 3T and 4T was performed using short-TE (15 ms) proton echo-planar spectroscopic imaging (PEPSI). Water-suppressed (WS) data were acquired in 8.5 min with 1-cm 3 spatial resolution from a supraventricular axial slice. Optimized outer volume suppression (OVS) enabled mapping in close proximity to peripheral scalp regions. Constrained spectral fitting in reference to a non-WS (NWS) scan was performed with LCModel using correction for relaxation attenuation and partial-volume effects. The concentrations of total choline (tCho), creatine ؉ phosphocreatine (Cr؉PCr), glutamate (Glu), glutamate ؉ glutamine (Glu؉Gln), myo-inositol (Ins), NAA, NAA؉NAAG, and two macromolecular resonances at 0.9 and 2.0 ppm were mapped with mean Cramer-Rao lower bounds (CRLBs) between 6% and 18% and ϳ150-cm 3 sensitive volumes. Aspartate, GABA, glutamine (Gln), glutathione (GSH), phosphoethanolamine (PE), and macromolecules (MMs) at 1.2 ppm were also mapped, although with larger mean CRLBs between 30% and 44%. The CRLBs at 4T were 19% lower on average as compared to 3T, consistent with a higher signal-to-noise ratio (SNR) and increased spectral resolution. Metabolite concentrations were in the ranges reported in previous studies. Glu concentration was significantly higher in gray matter (GM) compared to white matter ( Key words: magnetic resonance spectroscopic imaging; proton echo planar spectroscopic imaging; glutamate; spectral quantification; human brain Proton magnetic resonance spectroscopic mapping ( 1 H-MRSI) of brain metabolites can identify biomarkers relevant to psychiatric and neurological disease. There is currently increasing interest in extending 1 H-MRSI techniques and processing capabilities to map J-coupled brain metabolite resonances. Glutamate (Glu) and glutamine (Gln) mapping is of particular interest because these metabolites are key components of energy metabolism and nitrogen homeostasis pathways, and are also involved in excitatory synaptic neurotransmission (1). In vivo mapping of Glu in clinically feasible acquisition times may have important diagnostic applications in psychiatric disorders (2,3) and studies of aging (4).Thus far, Glu and Gln have been studied mostly by single-voxel MR spectroscopy (MRS) using a variety of techniques, including model-based fitting of short-TE spectra (4 -7), use of optimized intermediate TE (8) and Carr-Purcell refocusing pulses (9), spectral editing (10), and 2D J-resolved spectroscopy (11,12). MRSI studies of Glu and Gln have used spectral fitting at short TE (13,14), J-refocused coherence transfer (15), and, more recently, 2D J-resolved spectroscopic imaging (16,17). Spectral editing and 2D J-resolved MRSI techniques enable highly selective mapping of Glu and Gln, but they require multistep encoding, which prolongs the acquisition times and limits the sensitivity gains at high field, as metabolite T 2 values have been shown to decrease with field strength (18,19). Short-TE acquisition of single-voxel spect...

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Mild traumatic brain injury is the most prevalent neurological insult and frequently results in neurobehavioural sequelae. However, little is known about the pathophysiology underlying the injury and how these injuries change as a function of time. Although diffusion tensor imaging holds promise for in vivo characterization of white matter pathology, both the direction and magnitude of anisotropic water diffusion abnormalities in axonal tracts are actively debated. The current study therefore represents both an independent replication effort (n = 28) of our previous findings (n = 22) of increased fractional anisotropy during semi-acute injury, as well as a prospective study (n = 26) on the putative recovery of diffusion abnormalities. Moreover, new analytical strategies were applied to capture spatially heterogeneous white matter injuries, which minimize implicit assumptions of uniform injury across diverse clinical presentations. Results indicate that whereas a general pattern of high anisotropic diffusion/low radial diffusivity was present in various white matter tracts in both the replication and original cohorts, this pattern was only consistently observed in the genu of the corpus callosum across both samples. Evidence for a greater number of localized clusters with increased anisotropic diffusion was identified across both cohorts at trend levels, confirming heterogeneity in white matter injury. Pooled analyses (50 patients; 50 controls) suggested that measures of diffusion within the genu were predictive of patient classification, albeit at very modest levels (71% accuracy). Finally, we observed evidence of recovery in lesion load in returning patients across a 4-month interval, which was correlated with a reduction in self-reported post-concussive symptomatology. In summary, the corpus callosum may serve as a common point of injury in mild traumatic brain injury secondary to anatomical (high frequency of long unmyelinated fibres) and biomechanics factors. A spatially heterogeneous pattern of increased anisotropic diffusion exists in various other white matter tracts, and these white matter anomalies appear to diminish with recovery. This macroscopic pattern of diffusion abnormalities may be associated with cytotoxic oedema following mechanical forces, resulting in changes in ionic homeostasis, and alterations in the ratio of intracellular and extracellular water. Animal models more specific to the types of mild traumatic brain injury typically incurred by humans are needed to confirm the histological correlates of these macroscopic markers of white matter pathology.