Faculty Bibliography

Since mild traumatic brain injury (mTBI) often leads to neurological symptoms even without clinical MRI findings, our goal was to test whether diffuse axonal injury is quantifiable with multivoxel proton MR spectroscopic imaging ((1)H-MRSI). T1- and T2-weighted MRI images and three-dimensional (1)H-MRSI (480 voxels over 360 cm(3), about 30 % of the brain) were acquired at 3 T from 26 mTBI patients (mean Glasgow Coma Scale score 14.7, 18-56 years old, 3-55 days after injury) and 13 healthy matched contemporaries as controls. The N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) concentrations and gray-matter/white-matter (GM/WM) and cerebrospinal fluid fractions were obtained in each voxel. Global GM and WM absolute metabolic concentrations were estimated using linear regression, and patients were compared with controls using two-way analysis of variance. In patients, mean NAA, Cr, Cho and mI concentrations in GM (8.4 +/- 0.7, 6.9 +/- 0.6, 1.3 +/- 0.2, 5.5 +/- 0.6 mM) and Cr, Cho and mI in WM (4.8 +/- 0.5, 1.4 +/- 0.2, 4.6 +/- 0.7 mM) were not different from the values in controls. The NAA concentrations in WM, however, were significantly lower in patients than in controls (7.2 +/- 0.8 vs. 7.7 +/- 0.6 mM, p = 0.0125). The Cho and Cr levels in WM of patients were positively correlated with time since mTBI. This (1)H-MRSI approach allowed us to ascertain that early mTBI sequelae are (1) diffuse (not merely local), (2) neuronal (not glial), and (3) in the global WM (not GM). These findings support the hypothesis that, similar to more severe head trauma, mTBI also results in diffuse axonal injury, but that dysfunction rather than cell death dominates shortly after injury.

Purpose: Normal neuronal activity is tightly linked to and depends on the increase of blood flow for instantaneous supply of oxygen and glucose. This study is to evaluate whether there are cerebral blood flow (CBF) regulation abnormalities in MS with measurement of cerebrovascular reactivity (CVR) using hypercapnia perfusion MRI. Materials and Methods: Sixteen patients with MS (14 relapsing remitting and 2 secondary progressive) (mean age: 45.1+14.2 years, mean EDSS: 2.9+1.6) and age-matched 13 healthy controls (mean age: 44.5+12.2 years) were recruited for this study. CO2 is a potent vasodilator, and an increase of CO2 tension in blood (referred to as hypercapnia) is known to cause CBF increase. Such CBF changes were measured with a standard pseudo-continuous arterial spin labeling (pCASL) MRI at 3T, with quantitative CBF (ml/min/100g) maps generated during both room air and hypercapnia (mixed 5%CO2, 21%O2, and 74%N2) exposure. The imaging parameters of pCASL include TR/TE=3950/17ms, 52 repetitions, FOV=22cm, in-plane matrix=64x64, slice thickness=5mm, labeling duration=1500ms, postlabeling delay=1230ms, and label location = 84mm below AC-PC line. End-tidal CO2 (EtCO2) was recorded continuously during the scan with a capnograph device and was used as an input function in the analysis. The CVR was calculated as (% change in CBF comparing CO2 inhalation to room-air breathing) divided by (EtCO2 during CO2 inhalation - EtCO2 during room-air breathing). Segmented whole brain grey matter (GM), white matter (WM), and brain parenchymal CVR were calculated for the group analysis. Results: The averaged CVR (%CBF/mmHg EtCO2) showed significant difference for whole brain parenchymal (P=0.009), GM (P=0.008), and WM (P=0.03) between patients (4.74+0.88%, 4.89+1.08%, and 4.73+1.02%) and healthy controls (3.46+1.51%, 3.51+1.47%, and 3.53+1.83%, respectively). There was a significant correlation between brain parenchymal CVR and EDSS (r=-0.69, P=0.007). Whole brain CVR changes correlate with fractional brain p!

Purpose: To investigate the integrity of the default-mode network (DMN) by using independent component analysis (ICA) methods in patients shortly after mild traumatic brain injury (MTBI) and healthy control subjects, and to correlate DMN connectivity changes with neurocognitive tests and clinical symptoms. Materials and Methods: This study was approved by the institutional review board and complied with HIPAA regulations. Twenty-three patients with MTBI who had posttraumatic symptoms shortly after injury (<2 months) and 18 age-matched healthy control subjects were included in this study. Resting-state functional magnetic resonance imaging was performed at 3 T to characterize the DMN by using ICA methods, including a single-participant ICA on the basis of a comprehensive template from core seeds in the posterior cingulate cortex (PCC) and medial prefrontal cortex (MPFC) nodes. ICA z images of DMN components were compared between the two groups and correlated with neurocognitive tests and clinical performance in patients by using Pearson and Spearman rank correlation. Results: When compared with the control subjects, there was significantly reduced connectivity in the PCC and parietal regions and increased frontal connectivity around the MPFC in patients with MTBI (P < .01). These frontoposterior opposing changes within the DMN were significantly correlated (r = -0.44, P = .03). The reduced posterior connectivity correlated positively with neurocognitive dysfunction (eg, cognitive flexibility), while the increased frontal connectivity correlated negatively with posttraumatic symptoms (ie, depression, anxiety, fatigue, and postconcussion syndrome). Conclusion: These results showed abnormal DMN connectivity patterns in patients with MTBI, which may provide insight into how neuronal communication and information integration are disrupted among DMN key structures after mild head injury. (c) RSNA, 2012.

Since the brain's gray matter (GM) and white matter (WM) metabolite concentrations differ, their partial volumes can vary the voxel's (1) H MR spectroscopy ((1) H-MRS) signal, reducing sensitivity to changes. While single-voxel (1) H-MRS cannot differentiate between WM and GM signals, partial volume correction is feasible by MR spectroscopic imaging (MRSI) using segmentation of the MRI acquired for VOI placement. To determine the magnitude of this effect on metabolic quantification, we segmented a 1-mm(3) resolution MRI into GM, WM and CSF masks that were co-registered with the MRSI grid to yield their partial volumes in approximately every 1 cm(3) spectroscopic voxel. Each voxel then provided one equation with two unknowns: its i- metabolite's GM and WM concentrations C(i) (GM) , C(i) (WM) . With the voxels' GM and WM volumes as independent coefficients, the over-determined system of equations was solved for the global averaged C(i) (GM) and C(i) (WM) . Trading off local concentration differences offers three advantages: (i) higher sensitivity due to combined data from many voxels; (ii) improved specificity to WM versus GM changes; and (iii) reduced susceptibility to partial volume effects. These improvements made no additional demands on the protocol, measurement time or hardware. Applying this approach to 18 volunteered 3D MRSI sets of 480 voxels each yielded N-acetylaspartate, creatine, choline and myo-inositol C(i) (GM) concentrations of 8.5 +/- 0.7, 6.9 +/- 0.6, 1.2 +/- 0.2, 5.3 +/- 0.6mM, respectively, and C(i) (WM) concentrations of 7.7 +/- 0.6, 4.9 +/- 0.5, 1.4 +/- 0.1 and 4.4 +/- 0.6mM, respectively. We showed that unaccounted voxel WM or GM partial volume can vary absolute quantification by 5-10% (more for ratios), which can often double the sample size required to establish statistical significance

OBJECTIVES: To test the hypotheses that 1) patients with relapsing-remitting multiple sclerosis (RR-MS) exhibit a quantifiable decline in their whole-brain concentration of the neural marker N-acetyl-l-aspartate (WBNAA), that is 2) more sensitive than clinical changes and 3) may provide a practical outcome measure for proof-of-concept and larger phase III clinical trials. METHODS: Nineteen patients (5 men and 14 women) with clinically definite RR-MS, who were 33 +/- 5 years old (mean +/- SD), had a disease duration of 47 +/- 28 months, and had a median Expanded Disability Status Scale (EDSS) score of 1.0 (range 0-5.5), underwent MRI and proton magnetic resonance spectroscopy ((1)H-MRS) semiannually for 2 years (5 time points). Eight matched control subjects underwent the protocol annually (3 time points). Their global N-acetyl-l-aspartate (1)H-MRS signal was converted into absolute amounts by phantom replacement and into WBNAA by dividing with the brain parenchymal volume, V(B), from MRI segmentation. RESULTS: The baseline WBNAA of the patients (10.5 +/- 1.7 mM) was significantly lower than that of the controls (12.3 +/- 1.3 mM; p < 0.002) and declined significantly (5%/year, p < 0.002) vs that for the controls who did not show a decline (0.4%/year, p > 0.7). Likewise, V(B) values of the patients also declined significantly (0.5%/year, p < 0.0001), whereas those of the controls did not (0.2%/year, p = 0.08). The mean EDSS score of the patients increased insignificantly from 1.0 to 1.5 (range 0-6.0) and did not correlate with V(B) or WBNAA. CONCLUSIONS: WBNAA of patients with RR-MS declined significantly at both the group and individual levels over a 2-year time period common in clinical trials. Because of the small sample sizes required to establish power, WBNAA can be incorporated into future studies.

In this study, venous oxygen saturation and oxygen metabolic changes in multiple sclerosis (MS) patients were assessed using a recently developed T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging (MRI), which measures the superior sagittal venous sinus blood oxygenation (Yv) and cerebral metabolic rate of oxygen (CMRO(2)), an index of global oxygen consumption. Thirty patients with relapsing-remitting MS and 30 age-matched healthy controls were studied using TRUST at 3 T MR. The mean expanded disability status scale (EDSS) of the patients was 2.3 (range, 0 to 5.5). We found significantly increased Yv (P<0.0001) and decreased CMRO(2) (P=0.003) in MS patients (mean+/-s.d.: 65.9%+/-5.1% and 138.8+/-35.4 mumol per 100 g per minute) as compared with healthy control subjects (60.2%+/-4.0% and 180.2+/-24.8 mumol per 100 g per minute, respectively), implying decrease of oxygen consumption in MS. There was a significant positive correlation between Yv and EDSS and between Yv and lesion load in MS patients (n=30); on the contrary, there was a significant negative correlation between CMRO(2) and EDSS and between CMRO(2) and lesion load (n=12). There was no correlation between Yv and brain atrophy measures. This study showed preliminary evidence of the potential utility of TRUST in global oxygen metabolism. Our results of significant underutilization of oxygen in MS raise important questions regarding mitochondrial respiratory dysfunction and neurodegeneration of the disease.

Conventional imaging is unable to detect damage that accounts for permanent cognitive impairment in patients with mild traumatic brain injury (MTBI). While diffusion tensor imaging (DTI) can help to detect diffuse axonal injury (DAI), it is a limited indicator of tissue complexity. It has also been suggested that the thalamus may play an important role in the development of clinical sequelae in MTBI. The purpose of this study was to determine if diffusional kurtosis imaging (DKI), a novel quantitative magnetic resonance imaging (MRI) technique, can provide early detection of damage in the thalamus and white matter (WM) of MTBI patients and if thalamic injury is associated with cognitive impairment. Twenty-two MTBI patients and 14 controls underwent MRI and neuropsychological testing. Mean kurtosis (MK), fractional anisotropy (FA), and mean diffusivity (MD) were measured in the thalamus and several WM regions classically identified with DAI. Compared to controls, patients examined within one year after injury exhibited variously altered DTI and DKI derived measures in the thalamus and the internal capsule while, in addition to these regions, patients examined more than one year after injury also showed similar differences in the splenium of the corpus callosum and the centrum semiovale. Cognitive impairment was correlated to MK in the thalamus and the internal capsule. These findings suggest that combined use of DTI and DKI provides a more sensitive tool for identifying brain injury. In addition, MK in the thalamus might be useful for early prediction of permanent brain damage and cognitive outcome

BACKGROUND AND PURPOSE: Experimental studies have suggested a role for iron accumulation in the pathology of TBI. Magnetic field correlation MR imaging is sensitive to the presence of non-heme iron. The aims of this study are to 1) assess the presence, if any, and the extent of iron deposition in the deep gray matter and regional white matter of patients with mTBI by using MFC MR imaging; and 2) investigate the association of regional brain iron deposition with cognitive and behavioral performance of patients with mTBI. MATERIALS AND METHODS: We prospectively enrolled 28 patients with mTBI. Eighteen healthy subjects served as controls. The subjects were administered the Stroop color word test, the Verbal Fluency Task, and the Post-Concussion Symptoms Scale. The MR imaging protocol (on a 3T imager) consisted of conventional brain imaging and MFC sequences. After the calculation of parametric maps, MFC was measured by using a region of interest approach. MFC values across groups were compared by using analysis of covariance, and the relationship of MFC values and neuropsychological tests were evaluated by using Spearman correlations. RESULTS: Compared with controls, patients with mTBI demonstrated significant higher MFC values in the globus pallidus (P = .002) and in the thalamus (P = .036). In patients with mTBI, Stroop test scores were associated with the MFC value in frontal white matter (r = -0.38, P = .043). CONCLUSIONS: MFC values were significantly elevated in the thalamus and globus pallidus of patients with mTBI, suggesting increased accumulation of iron. This supports the hypothesis that deep gray matter is a site of injury in mTBI and suggests a possible role for iron accumulation in the pathophysiological events after mTBI