Characterizing Brain Structures and Remodeling after TBI Based on Information Content,Diffusion Entropy

Background

To overcome the limitations of conventional diffusion tensor magnetic resonance imaging resulting from the assumption of a Gaussian diffusion model for characterizing voxels containing multiple axonal orientations, Shannon''s entropy was employed to evaluate white matter structure in human brain and in brain remodeling after traumatic brain injury (TBI) in a rat.

Methods

Thirteen healthy subjects were investigated using a Q-ball based DTI data sampling scheme. FA and entropy values were measured in white matter bundles, white matter fiber crossing areas, different gray matter (GM) regions and cerebrospinal fluid (CSF). Axonal densities'' from the same regions of interest (ROIs) were evaluated in Bielschowsky and Luxol fast blue stained autopsy (n = 30) brain sections by light microscopy. As a case demonstration, a Wistar rat subjected to TBI and treated with bone marrow stromal cells (MSC) 1 week after TBI was employed to illustrate the superior ability of entropy over FA in detecting reorganized crossing axonal bundles as confirmed by histological analysis with Bielschowsky and Luxol fast blue staining.

Results

Unlike FA, entropy was less affected by axonal orientation and more affected by axonal density. A significant agreement (r = 0.91) was detected between entropy values from in vivo human brain and histologically measured axonal density from post mortum from the same brain structures. The MSC treated TBI rat demonstrated that the entropy approach is superior to FA in detecting axonal remodeling after injury. Compared with FA, entropy detected new axonal remodeling regions with crossing axons, confirmed with immunohistological staining.

Conclusions

Entropy measurement is more effective in distinguishing axonal remodeling after injury, when compared with FA. Entropy is also more sensitive to axonal density than axonal orientation, and thus may provide a more accurate reflection of axonal changes that occur in neurological injury and disease.     

Early Detection of Ventilation-Induced Brain Injury Using Magnetic Resonance Spectroscopy and Diffusion Tensor Imaging: An In Vivo Study in Preterm Lambs

Background and Aim

High tidal volume (V_T) ventilation during resuscitation of preterm lambs results in brain injury evident histologically within hours after birth. We aimed to investigate whether magnetic resonance spectroscopy (MRS) and/or diffusion tensor imaging (DTI) can be used for early in vivo detection of ventilation-induced brain injury in preterm lambs.

Methods

Newborn lambs (0.85 gestation) were stabilized with a “protective ventilation” strategy (PROT, n = 7: prophylactic Curosurf, sustained inflation, V_T 7 mL/kg, positive end expiratory pressure (PEEP) 5 cmH₂O) or an initial 15 minutes of “injurious ventilation” (INJ, n = 10: V_T 12 mL/kg, no PEEP, late Curosurf) followed by PROT ventilation for the remainder of the experiment. At 1 hour, lambs underwent structural magnetic resonance imaging (Siemens, 3 Tesla). For measures of mean/axial/radial diffusivity (MD, AD, RD) and fractional anisotropy (FA), 30 direction DTI was performed. Regions of interests encompassed the thalamus, internal capsule, periventricular white matter and the cerebellar vermis. MRS was performed using a localized single-voxel (15×15×20 mm³, echo time 270 ms) encompassing suptratentorial deep nuclear grey matter and central white matter. Peak-area ratios for lactate (Lac) relative to N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) were calculated. Groups were compared using 2-way RM-ANOVA, Mann-Whitney U-test and Spearman''s correlations.

Results

No cerebral injury was seen on structural MR images. Lambs in the INJ group had higher mean FA and lower mean RD in the thalamus compared to PROT lambs, but not in the other regions of interest. Peak-area lactate ratios >1.0 was only seen in INJ lambs. A trend of higher mean peak-area ratios for Lac/Cr and Lac/Cho was seen, which correlated with lower pH in both groups.

Conclusion

Acute changes in brain diffusion measures and metabolite peak-area ratios were observed after injurious ventilation. Early MRS/DTI is able to detect the initiation of ventilation-induced brain injury.     

Whole Brain Approaches for Identification of Microstructural Abnormalities in Individual Patients: Comparison of Techniques Applied to Mild Traumatic Brain Injury

Purpose

Group-wise analyses of DTI in mTBI have demonstrated evidence of traumatic axonal injury (TAI), associated with adverse clinical outcomes. Although mTBI is likely to have a unique spatial pattern in each patient, group analyses implicitly assume that location of injury will be the same across patients. The purpose of this study was to optimize and validate a procedure for analysis of DTI images acquired in individual patients, which could detect inter-individual differences and be applied in the clinical setting, where patients must be assessed as individuals.

Materials and Methods

After informed consent and in compliance with HIPAA, 34 mTBI patients and 42 normal subjects underwent 3.0 Tesla DTI. Four voxelwise assessment methods (standard Z-score, “one vs. many” t-test, Family-Wise Error Rate control using pseudo t-distribution, EZ-MAP) for use in individual patients, were applied to each patient’s fractional anisotropy (FA) maps and tested for its ability to discriminate patients from controls. Receiver Operating Characteristic (ROC) analyses were used to define optimal thresholds (voxel-level significance and spatial extent) for reliable and robust detection of mTBI pathology.

Results

ROC analyses showed EZ-MAP (specificity 71%, sensitivity 71%), “one vs. many” t-test and standard Z-score (sensitivity 65%, specificity 76% for both methods) resulted in a significant area under the curve (AUC) score for discriminating mTBI patients from controls in terms of the total number of abnormal white matter voxels detected while the FWER test was not significant. EZ-MAP is demonstrated to be robust to assumptions of Gaussian behavior and may serve as an alternative to methods that require strict Gaussian assumptions.

Conclusion

EZ-MAP provides a robust approach for delineation of regional abnormal anisotropy in individual mTBI patients.     

Combining Biochemical and Imaging Markers to Improve Diagnosis and Characterization of Mild Traumatic Brain Injury in the Acute Setting: Results from a Pilot Study

Background

Mild traumatic brain injury (mTBI) is a significant healthcare burden and its diagnosis remains a challenge in the emergency department. Serum biomarkers and advanced magnetic resonance imaging (MRI) techniques have already demonstrated their potential to improve the detection of brain injury even in patients with negative computed tomography (CT) findings. The objective of this study was to determine the clinical value of a combinational use of both blood biomarkers and MRI in mTBI detection and their characterization in the acute setting (within 24 hours after injury).

Methods

Nine patients with mTBI were prospectively recruited from the emergency department. Serum samples were collected at the time of hospital admission and every 6 hours up to 24 hours post injury. Neuronal (Ubiquitin C-terminal Hydrolase-L1 [UCH-L1]) and glial (glial fibrillary acidic protein [GFAP]) biomarker levels were analyzed. Advanced MRI data were acquired at 9±6.91 hours after injury. Patients’ neurocognitive status was assessed by using the Standard Assessment of Concussion (SAC) instrument.

Results

The median serum levels of UCH-L1 and GFAP on admission were increased 4.9 folds and 10.6 folds, respectively, compared to reference values. Three patients were found to have intracranial hemorrhages on SWI, all of whom had very high GFAP levels. Total volume of brain white matter (WM) with abnormal fractional anisotropy (FA) measures of diffusion tensor imaging (DTI) were negatively correlated with patients’ SAC scores, including delayed recall. Both increased and decreased DTI-FA values were observed in the same subjects. Serum biomarker level was not correlated with patients’ DTI data nor SAC score.

Conclusions

Blood biomarkers and advanced MRI may correlate or complement each other in different aspects of mTBI detection and characterization. GFAP might have potential to serve as a clinical screening tool for intracranial bleeding. UCH-L1 complements MRI in injury detection. Impairment at WM tracts may account for the patients’ neurocognitive symptoms.     

White matter correlates of neuropsychological dysfunction in systemic lupus erythematosus

Patients diagnosed with Systemic Lupus Erythematosus have similar levels of neuropsychological dysfunction (i.e., 20–50%) as those with Neuropsychiatric Systemic Lupus Erythematosus (NPSLE). We hypothesized a gradient between cognition and white matter integrity, such that strongest brain-behavior relationships would emerge in NPSLE, intermediate in non-NPSLE, and minimal in controls. We studied thirty-one patients (16 non-NPSLE; 15 NPSLE), ranging in age from 18 to 59 years old (100% female), and eighteen age and gender matched healthy controls. DTI examinations were performed on a 1.5T scanner. A broad neuropsychological battery was administered, tapping attention, memory, processing speed, and executive functioning. The Total z-score consisted of the combined sum of all neuropsychological measures. In control subjects, we found no significant FA-Total z-score correlations. NPSLE, non-NPSLE, and control subjects differed significantly in terms of Total z-score (NPSLE = −2.25+/−1.77, non-NPSLE = −1.22+/−1.03, Controls = −0.10+/−.57; F = 13.2, p<.001). In non-NPSLE subjects, FA within the right external capsule was significantly correlated with Total z-score. In NPSLE subjects, the largest FA-Total z-score clusters were observed within the left anterior thalamic radiation and right superior longitudinal fasciculus. In subsequent analyses the largest number of significant voxels linked FA with the Processing Speed z-score in NPSLE. The current results reflect objective white matter correlates of neuropsychological dysfunction in both NPSLE and (to a lesser degree) in non-NPSLE. non-NPSLE and NPSLE subjects did not differ significantly in terms of depression, as measured by the GDI; thus, previous hypotheses suggesting moderating effects of depression upon neuropsychological performance do not impact the current FA results.     

Degeneration of the Injured Cervical Cord Is Associated with Remote Changes in Corticospinal Tract Integrity and Upper Limb Impairment

Background

Traumatic spinal cord injury (SCI) leads to disruption of axons and macroscopic tissue loss. Using diffusion tensor imaging (DTI), we assessed degeneration of the corticospinal tract (CST) in the cervical cord above a traumatic lesion and explored its relationship with cervical atrophy, remote axonal changes within the cranial CST and upper limb function.

Methods

Nine cervical injured volunteers with bilateral motor and sensory impairment and ten controls were studied. DTI of the cervical cord and brain provided measurements of fractional anisotropy (FA), while anatomical MRI assessed cross-sectional spinal cord area (i.e. cord atrophy). Spinal and central regions of interest (ROI) included the bilateral CST in the cervical cord and brain. Regression analysis identified correlations between spinal FA and cranial FA in the CST and disability.

Results

In individuals with SCI, FA was significantly lower in both CSTs throughout the cervical cord and brain when compared with controls (p≤0.05). Reduced FA of the cervical cord in patients with SCI was associated with smaller cord area (p = 0.002) and a lower FA of the cranial CST at the internal capsule level (p = 0.001). Lower FA in the cervical CST also correlated with impaired upper limb function, independent of cord area (p = 0.03).

Conclusion

Axonal degeneration of the CST in the atrophic cervical cord, proximal to the site of injury, parallels cranial CST degeneration and is associated with disability. This DTI protocol can be used in longitudinal assessment of microstructural changes immediately following injury and may be utilised to predict progression and monitor interventions aimed at promoting spinal cord repair.     

MR-Less Surface-Based Amyloid Assessment Based on 11C PiB PET

Background

β-amyloid (Aβ) plaques in brain''s grey matter (GM) are one of the pathological hallmarks of Alzheimer''s disease (AD), and can be imaged in vivo using Positron Emission Tomography (PET) with ¹¹C or ¹⁸F radiotracers. Estimating Aβ burden in cortical GM has been shown to improve diagnosis and monitoring of AD. However, lacking structural information in PET images requires such assessments to be performed with anatomical MRI scans, which may not be available at different clinical settings or being contraindicated for particular reasons. This study aimed to develop an MR-less Aβ imaging quantification method that requires only PET images for reliable Aβ burden estimations.

Materials and Methods

The proposed method has been developed using a multi-atlas based approach on ¹¹C-PiB scans from 143 subjects (75 PiB+ and 68 PiB- subjects) in AIBL study. A subset of 20 subjects (PET and MRI) were used as atlases: 1) MRI images were co-registered with tissue segmentation; 2) 3D surface at the GM-WM interfacing was extracted and registered to a canonical space; 3) Mean PiB retention within GM was estimated and mapped to the surface. For other participants, each atlas PET image (and surface) was registered to the subject''s PET image for PiB estimation within GM. The results are combined by subject-specific atlas selection and Bayesian fusion to generate estimated surface values.

Results

All PiB+ subjects (N = 75) were highly correlated between the MR-dependent and the PET-only methods with Intraclass Correlation (ICC) of 0.94, and an average relative difference error of 13% (or 0.23 SUVR) per surface vertex. All PiB- subjects (N = 68) revealed visually akin patterns with a relative difference error of 16% (or 0.19 SUVR) per surface vertex.

Conclusion

The demonstrated accuracy suggests that the proposed method could be an effective clinical inspection tool for Aβ imaging scans when MRI images are unavailable.     

Reduced Right Frontal Fractional Anisotropy Correlated with Early Elevated Plasma LDL Levels in Obese Young Adults

Objective

To investigate the underlying physiological mechanisms of the structural differences in gray matter (GM) and white matter (WM) associated with obesity in young Chinese adults.

Materials and Methods

A total of 49 right-handed obese or overweight (n = 22, mean age 31.72±8.04 years) and normal weight (n = 27, mean age 29.04±7.32 years) Han Chinese individuals were recruited. All participants underwent voxel-based morphometry analysis of T1-weighted MRI and tract-based spatial statistics analysis of diffusion tensor imaging. Partial correlation analysis was performed between the physiological data obtained and the abnormal structural alterations.

Results

In the OO group, GM atrophy occurred in the left prefrontal cortex, bilateral cingulate gyrus, and the right temporal lobe, while enlargement was observed in the bilateral putamen. WM atrophy was observed predominantly in the regions that regulate food intake, such as the bilateral basal ganglia, the right amygdala, and the left insula. The OO group exhibited lower fractional anisotropy (FA) in bilateral frontal corticospinal tracts and the right brainstem. Significant negative correlations were observed between FA values of those three clusters and BMI, and waist circumference, while the volume of bilateral putamen positively correlated with both BMI and waist circumference. High plasma LDL levels were correlated with low FA values in the right frontal corticospinal tract. Interestingly, the negative correlation was limited to male participants.

Conclusions

Obesity-related alterations of GM and WM volumes were observed predominantly in food reward circuit, which may motivate abnormal dietary intake. Further, early elevated plasma LDL might contribute to low right frontal FA values of male adults, which requires further demonstration by larger-scale and longitudinal studies.     

MRI of Neuronal Recovery after Low-Dose Methamphetamine Treatment of Traumatic Brain Injury in Rats

We assessed the effects of low dose methamphetamine treatment of traumatic brain injury (TBI) in rats by employing MRI, immunohistology, and neurological functional tests. Young male Wistar rats were subjected to TBI using the controlled cortical impact model. The treated rats (n = 10) received an intravenous (iv) bolus dose of 0.42 mg/kg of methamphetamine at eight hours after the TBI followed by continuous iv infusion for 24 hrs. The control rats (n = 10) received the same volume of saline using the same protocol. MRI scans, including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), were performed one day prior to TBI, and at 1 and 3 days post TBI, and then weekly for 6 weeks. The lesion volumes of TBI damaged cerebral tissue were demarcated by elevated values in T₂ maps and were histologically identified by hematoxylin and eosin (H&E) staining. The fractional anisotropy (FA) values within regions-of-interest (ROI) were measured in FA maps deduced from DTI, and were directly compared with Bielschowsky’s silver and Luxol fast blue (BLFB) immunohistological staining. No therapeutic effect on lesion volumes was detected during 6 weeks after TBI. However, treatment significantly increased FA values in the recovery ROI compared with the control group at 5 and 6 weeks after TBI. Myelinated axons histologically measured using BLFB were significantly increased (p<0.001) in the treated group (25.84±1.41%) compared with the control group (17.05±2.95%). Significant correlations were detected between FA and BLFB measures in the recovery ROI (R = 0.54, p<0.02). Methamphetamine treatment significantly reduced modified neurological severity scores from 2 to 6 weeks (p<0.05) and foot-fault errors from 3 days to 6 weeks (p<0.05) after TBI. Thus, the FA data suggest that methamphetamine treatment improves white matter reorganization from 5 to 6 weeks after TBI in rats compared with saline treatment, which may contribute to the observed functional recovery.     

Tractography of the Brainstem in Major Depressive Disorder Using Diffusion Tensor Imaging

Background

The brainstem is the main region that innervates neurotransmitter release to the Hypothalamic-Pituitary Adrenal (HPA) axis and fronto-limbic circuits, two key brain circuits found to be dysfunctional in Major Depressive Disorder (MDD). However, the brainstem’s role in MDD has only been evaluated in limited reports. Using Diffusion Tensor Imaging (DTI), we investigated whether major brainstem white matter tracts that relate to these two circuits differ in MDD patients compared to healthy controls.

Methods

MDD patients (n = 95) and age- and gender-matched controls (n = 34) were assessed using probabilistic tractography of DTI to delineate three distinct brainstem tracts: the nigrostriatal tract (connecting brainstem to striatum), solitary tract (connecting brainstem to amygdala) and corticospinal tract (connecting brainstem to precentral cortex). Fractional anisotropy (FA) was used to measure the white matter integrity of these tracts, and measures were compared between MDD and control participants.

Results

MDD participants were characterized by a significant and specific decrease in white matter integrity of the right solitary tract (p<0.009 using independent t-test), which is a “bottom up” afferent pathway that connects the brainstem to the amygdala. This decrease was not related to symptom severity.

Conclusions

The results provide new evidence to suggest that structural connectivity between the brainstem and the amygdala is altered in MDD. These results are interesting in light of predominant theories regarding amygdala-mediated emotional reactivity observed in functional imaging studies of MDD. The characterization of altered white matter integrity in the solitary tract in MDD supports the possibility of dysfunctional brainstem-amygdala connectivity impacting vulnerable circuits in MDD.     

Use of Brain MRI Atlases to Determine Boundaries of Age-Related Pathology: The Importance of Statistical Method

IntroductionNeurodegenerative disease diagnoses may be supported by the comparison of an individual patient’s brain magnetic resonance image (MRI) with a voxel-based atlas of normal brain MRI. Most current brain MRI atlases are of young to middle-aged adults and parametric, e.g., mean ±standard deviation (SD); these atlases require data to be Gaussian. Brain MRI data, e.g., grey matter (GM) proportion images, from normal older subjects are apparently not Gaussian. We created a nonparametric and a parametric atlas of the normal limits of GM proportions in older subjects and compared their classifications of GM proportions in Alzheimer’s disease (AD) patients.MethodsUsing publicly available brain MRI from 138 normal subjects and 138 subjects diagnosed with AD (all 55–90 years), we created: a mean ±SD atlas to estimate parametrically the percentile ranks and limits of normal ageing GM; and, separately, a nonparametric, rank order-based GM atlas from the same normal ageing subjects. GM images from AD patients were then classified with respect to each atlas to determine the effect statistical distributions had on classifications of proportions of GM in AD patients.ResultsThe parametric atlas often defined the lower normal limit of the proportion of GM to be negative (which does not make sense physiologically as the lowest possible proportion is zero). Because of this, for approximately half of the AD subjects, 25–45% of voxels were classified as normal when compared to the parametric atlas; but were classified as abnormal when compared to the nonparametric atlas. These voxels were mainly concentrated in the frontal and occipital lobes.DiscussionTo our knowledge, we have presented the first nonparametric brain MRI atlas. In conditions where there is increasing variability in brain structure, such as in old age, nonparametric brain MRI atlases may represent the limits of normal brain structure more accurately than parametric approaches. Therefore, we conclude that the statistical method used for construction of brain MRI atlases should be selected taking into account the population and aim under study. Parametric methods are generally robust for defining central tendencies, e.g., means, of brain structure. Nonparametric methods are advisable when studying the limits of brain structure in ageing and neurodegenerative disease.     

Efficacy of Distortion Correction on Diffusion Imaging: Comparison of FSL Eddy and Eddy_Correct Using 30 and 60 Directions Diffusion Encoding

Diffusion imaging is a unique noninvasive tool to detect brain white matter trajectory and integrity in vivo. However, this technique suffers from spatial distortion and signal pileup or dropout originating from local susceptibility gradients and eddy currents. Although there are several methods to mitigate these problems, most techniques can be applicable either to susceptibility or eddy-current induced distortion alone with a few exceptions. The present study compared the correction efficiency of FSL tools, “eddy_correct” and the combination of “eddy” and “topup” in terms of diffusion-derived fractional anisotropy (FA). The brain diffusion images were acquired from 10 healthy subjects using 30 and 60 directions encoding schemes based on the electrostatic repulsive forces. For the 30 directions encoding, 2 sets of diffusion images were acquired with the same parameters, except for the phase-encode blips which had opposing polarities along the anteroposterior direction. For the 60 directions encoding, non–diffusion-weighted and diffusion-weighted images were obtained with forward phase-encoding blips and non–diffusion-weighted images with the same parameter, except for the phase-encode blips, which had opposing polarities. FA images without and with distortion correction were compared in a voxel-wise manner with tract-based spatial statistics. We showed that images corrected with eddy and topup possessed higher FA values than images uncorrected and corrected with eddy_correct with trilinear (FSL default setting) or spline interpolation in most white matter skeletons, using both encoding schemes. Furthermore, the 60 directions encoding scheme was superior as measured by increased FA values to the 30 directions encoding scheme, despite comparable acquisition time. This study supports the combination of eddy and topup as a superior correction tool in diffusion imaging rather than the eddy_correct tool, especially with trilinear interpolation, using 60 directions encoding scheme.     

MRI Evidence for Altered Venous Drainage and Intracranial Compliance in Mild Traumatic Brain Injury

Purpose

To compare venous drainage patterns and associated intracranial hydrodynamics between subjects who experienced mild traumatic brain injury (mTBI) and age- and gender-matched controls.

Methods

Thirty adult subjects (15 with mTBI and 15 age- and gender-matched controls) were investigated using a 3T MR scanner. Time since trauma was 0.5 to 29 years (mean 11.4 years). A 2D-time-of-flight MR-venography of the upper neck was performed to visualize the cervical venous vasculature. Cerebral venous drainage through primary and secondary channels, and intracranial compliance index and pressure were derived using cine-phase contrast imaging of the cerebral arterial inflow, venous outflow, and the craniospinal CSF flow. The intracranial compliance index is the defined as the ratio of maximal intracranial volume and pressure changes during the cardiac cycle. MR estimated ICP was then obtained through the inverse relationship between compliance and ICP.

Results

Compared to the controls, subjects with mTBI demonstrated a significantly smaller percentage of venous outflow through internal jugular veins (60.9±21% vs. controls: 76.8±10%; p = 0.01) compensated by an increased drainage through secondary veins (12.3±10.9% vs. 5.5±3.3%; p<0.03). Mean intracranial compliance index was significantly lower in the mTBI cohort (5.8±1.4 vs. controls 8.4±1.9; p<0.0007). Consequently, MR estimate of intracranial pressure was significantly higher in the mTBI cohort (12.5±2.9 mmHg vs. 8.8±2.0 mmHg; p<0.0007).

Conclusions

mTBI is associated with increased venous drainage through secondary pathways. This reflects higher outflow impedance, which may explain the finding of reduced intracranial compliance. These results suggest that hemodynamic and hydrodynamic changes following mTBI persist even in the absence of clinical symptoms and abnormal findings in conventional MR imaging.     

Quantitative analysis of brain microstructure following mild blunt and blast trauma

We induced mild blunt and blast injuries in rats using a custom-built device and utilized in-house diffusion tensor imaging (DTI) software to reconstruct 3-D fiber tracts in brains before and after injury (1, 4, and 7 days). DTI measures such as fiber count, fiber length, and fractional anisotropy (FA) were selected to characterize axonal integrity. In-house image analysis software also showed changes in parameters including the area fraction (AF) and nearest neighbor distance (NND), which corresponded to variations in the microstructure of Hematoxylin and Eosin (H&E) brain sections. Both blunt and blast injuries produced lower fiber counts, but neither injury case significantly changed the fiber length. Compared to controls, blunt injury produced a lower FA, which may correspond to an early onset of diffuse axonal injury (DAI). However, blast injury generated a higher FA compared to controls. This increase in FA has been linked previously to various phenomena including edema, neuroplasticity, and even recovery. Subsequent image analysis revealed that both blunt and blast injuries produced a significantly higher AF and significantly lower NND, which correlated to voids formed by the reduced fluid retention within injured axons. In conclusion, DTI can detect subtle pathophysiological changes in axonal fiber structure after mild blunt and blast trauma. Our injury model and DTI method provide a practical basis for studying mild traumatic brain injury (mTBI) in a controllable manner and for tracking injury progression. Knowledge gained from our approach could lead to enhanced mTBI diagnoses, biofidelic constitutive brain models, and specialized pharmaceutical treatments.     

Altered Glutamatergic Metabolism Associated with Punctate White Matter Lesions in Preterm Infants

Preterm infants (∼10% of all births) are at high-risk for long-term neurodevelopmental disabilities, most often resulting from white matter injury sustained during the neonatal period. Glutamate excitotoxicity is hypothesized to be a key mechanism in the pathogenesis of white matter injury; however, there has been no in vivo demonstration of glutamate excitotoxicity in preterm infants. Using magnetic resonance spectroscopy (MRS), we tested the hypothesis that glutamate and glutamine, i.e., markers of glutamatergic metabolism, are altered in association with punctate white matter lesions and “diffuse excessive high signal intensity” (DEHSI), the predominant patterns of preterm white matter injury. We reviewed all clinically-indicated MRS studies conducted on preterm infants at a single institution during a six-year period and determined the absolute concentration of glutamate, glutamine, and four other key metabolites in the parietal white matter in 108 of those infants after two investigators independently evaluated the studies for punctate white matter lesions and DEHSI. Punctate white matter lesions were associated with a 29% increase in glutamine concentration (p = 0.002). In contrast, there were no differences in glutamatergic metabolism in association with DEHSI. Severe DEHSI, however, was associated with increased lactate concentration (p = 0.001), a marker of tissue acidosis. Findings from this study support glutamate excitotoxicity in the pathogenesis of punctate white matter lesions, but not necessarily in DEHSI, and suggest that MRS provides a useful biomarker for determining the pathogenesis of white matter injury in preterm infants during a period when neuroprotective agents may be especially effective.     

Progressive Levels of Physical Dependence to Tobacco Coincide with Changes in the Anterior Cingulum Bundle Microstructure

Background

The tobacco withdrawal syndrome indicates the development of neurophysiologic dependence. Clinical evidence indicates that neurophysiologic dependence develops through a set sequence of symptom presentation that can be assessed with a new 3-item survey measure of wanting, craving, and needing tobacco, the Level of Physical Dependence (PD). This study sought to determine if advancing neurophysiologic dependence as measured by the Level of PD correlates with characteristics of white matter structure measured by Fractional Anisotropy (FA).

Methods

Diffusion-MRI based FA and diffusion tensor imaging probabilistic tractography were used to evaluate 11 smokers and 10 nonsmokers. FA was also examined in relation to two additional measures of dependence severity, the Hooked on Nicotine Checklist (HONC), and the Fagerström Test for Nicotine Dependence (FTND).

Results

Among smokers, FA in the left anterior cingulate bundle (ACb) correlated negatively with the Level of PD (r = −0.68, p = 0.02) and HONC scores (r = −0.65, p = 0.03), but the correlation for the FTND did not reach statistical significance (r = −49, p = 0.12). With advancing Levels of PD, the density of streamlines between the ACb and precuneus increased (r = −0.67, p<0.05) and those between the ACb and white matter projecting to the superior-frontal cortex (r = −0.86, p = 0.0006) decreased significantly.

Conclusions

The correlations between neural structure and both the clinical Level of PD survey measure and the HONC suggest that the Level of PD and the HONC may reflect the microstructural integrity of white matter, as influenced by tobacco abuse. Given that the Level of PD is measuring a sequence of symptoms of neurophysiologic dependence that develops over time, the correlation between the Level of PD and neural structure suggests that these features might represent neuroplastic changes that develop over time to support the development of neurophysiologic dependence.     

Early-Stage Psychotherapy Produces Elevated Frontal White Matter Integrity in Adult Major Depressive Disorder

Background

Psychotherapy has demonstrated comparable efficacy to antidepressant medication in the treatment of major depressive disorder. Metabolic alterations in the MDD state and in response to treatment have been detected by functional imaging methods, but the underlying white matter microstructural changes remain unknown. The goal of this study is to apply diffusion tensor imaging techniques to investigate psychotherapy-specific responses in the white matter.

Methods

Twenty-one of forty-five outpatients diagnosed with major depression underwent diffusion tensor imaging before and after a four-week course of guided imagery psychotherapy. We compared fractional anisotropy in depressed patients (n = 21) with healthy controls (n = 22), and before-after treatment, using whole brain voxel-wise analysis.

Results

Post-treatment, depressed subjects showed a significant reduction in the 17-item Hamilton Depression Rating Scale. As compared to healthy controls, depressed subjects demonstrated significantly increased fractional anisotropy in the right thalamus. Psychopathological changes did not recover post-treatment, but a novel region of increased fractional anisotropy was discovered in the frontal lobe.

Conclusions

At an early stage of psychotherapy, higher fractional anisotropy was detected in the frontal emotional regulation-associated region. This finding reveals that psychotherapy may induce white matter changes in the frontal lobe. This remodeling of frontal connections within mood regulation networks positively contributes to the “top-down” mechanism of psychotherapy.     

The Value of Diffusion Tensor Imaging in Differentiating High-Grade Gliomas from Brain Metastases: A Systematic Review and Meta-Analysis

Purpose

Differentiation of high-grade gliomas and solitary brain metastases is an important clinical issue because the treatment strategies differ greatly. Our study aimed to investigate the potential value of diffusion tensor imaging (DTI) in differentiating high-grade gliomas from brain metastases using a meta-analytic approach.

Materials and Methods

We searched Pubmed, Embase and the Cochrane Library for relevant articles published in English. Studies that both investigated high-grade gliomas and brain metastases using DTI were included. Random effect model was used to compare fractional anisotropy (FA) and mean diffusivity (MD) values in the two tumor entities.

Results

Nine studies were included into the meta-analysis. In the peritumoral region, compared with brain metastases, high-grade gliomas had a significant increase of FA (SMD  = 0.47; 95% CI, 0.22–0.71; P<0.01) and a significant decrease of MD (SMD  = −1.49; 95% CI, −1.91 to −1.06; P<0.01). However, in the intratumoral area, no significant change in FA (SMD  = 0.16; 95% CI, −0.49 to 0.82; P = 0.73) or MD (SMD  = 0.34; 95% CI, −0.91 to 1.60; P = 0.59) was detected between gliomas and metastases.

Conclusions

High-grade gliomas may be distinguished from brain metastases by comparing the peritumoral FA and MD values. DTI appears to be a promising tool in diagnosing solitary intracranial lesions.     

Identification of Neonatal White Matter on DTI: Influence of More Inclusive Thresholds for Atlas Segmentation

Purpose

Semi-automated diffusion tensor imaging (DTI) analysis of white matter (WM) microstructure offers a clinically feasible technique to assess neonatal brain development and provide early prognosis, but is limited by variable methods and insufficient evidence regarding optimal parameters. The purpose of this research was to investigate the influence of threshold values on semi-automated, atlas-based brain segmentation in very-low-birth-weight (VLBW) preterm infants at near-term age.

Materials and Methods

DTI scans were analyzed from 45 VLBW preterm neonates at near-term-age with no brain abnormalities evident on MRI. Brain regions were selected with a neonatal brain atlas and threshold values: trace <0.006 mm²/s, fractional anisotropy (FA)>0.15, FA>0.20, and FA>0.25. Relative regional volumes, FA, axial diffusivity (AD), and radial diffusivity (RD) were compared for twelve WM regions.

Results

Near-term brain regions demonstrated differential effects from segmentation with the three FA thresholds. Regional DTI values and volumes selected in the PLIC, CereP, and RLC varied the least with the application of different FA thresholds. Overall, application of higher FA thresholds significantly reduced brain region volume selected, increased variability, and resulted in higher FA and lower RD values. The lower threshold FA>0.15 selected 78±21% of original volumes segmented by the atlas, compared to 38±12% using threshold FA>0.25.

Conclusion

Results indicate substantial and differential effects of atlas-based DTI threshold parameters on regional volume and diffusion scalars. A lower, more inclusive FA threshold than typically applied for adults is suggested for consistent analysis of WM regions in neonates.