Additive effects of mild head trauma, blast exposure, and aging within white matter tracts: A novel Diffusion Tensor Imaging analysis approach.

Existing diffusion tensor imaging (DTI) studies of neurological injury following high-level blast exposure (hlBE) in military personnel have produced widely variable results. This is potentially due to prior studies often not considering the quantity and/or recency of hlBE, as well as co-morbidity with non-blast head trauma (nbHT). Herein, we compare commonly used DTI metrics: fractional anisotropy and mean, axial, and radial diffusivity, in Veterans with and without history of hlBE and/or nbHT. We use both the traditional method of dividing participants into 2 equally weighted groups and an alternative method wherein each participant is weighted by quantity and recency of hlBE and/or nbHT. While no differences were detected using the traditional method, the alternative method revealed diffuse and extensive changes in all DTI metrics. These effects were quantified within 43 anatomically defined white matter tracts, which identified the forceps minor, middle corpus callosum, acoustic and optic radiations, fornix, uncinate, inferior fronto-occipital and inferior longitudinal fasciculi, and cingulum, as the pathways most affected by hlBE and nbHT. Moreover, additive effects of aging were present in many of the same tracts suggesting that these neuroanatomical effects may compound with age.

The acute effects of repetitive transcranial magnetic stimulation on laminar diffusion anisotropy of neocortical gray matter.

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used to treat neuropsychiatric disorders. Inhibitory and excitatory regimens have been both adopted but the exact mechanism of action remains unclear, and investigating their differential effects on laminar diffusion profiles of neocortex may add important evidence. Twenty healthy participants were randomly assigned to receive a low-frequency/inhibitory or high-frequency/excitatory rTMS targeting the left dorsolateral prefrontal cortex (DLPFC). With the brand-new submillimeter diffusion tensor imaging of whole brain and specialized surface-based laminar analysis, fractional anisotropy (FA) and mean diffusion (MD) profiles of cortical layers at different cortical depths were characterized before/after rTMS. Inhibitory and excitatory rTMS both showed impacts on diffusion metrics of somatosensory, limbic, and sensory regions, but different patterns of changes were observed-increased FA with inhibitory rTMS, whereas decreased FA with excitatory rTMS. More importantly, laminar analysis indicated laminar specificity of changes in somatosensory regions during different rTMS patterns-inhibitory rTMS affected the superficial layers contralateral to the DLPFC, while excitatory rTMS led to changes in the intermediate/deep layers bilateral to the DLPFC. These findings provide novel insights into acute neurobiological effects on diffusion profiles of rTMS that may add critical evidence relevant to different protocols of rTMS on neocortex.

Diffusion kurtosis imaging and diffusion weighted imaging comparison in diagnosis of early hypoxic-ischemic brain edema.

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) refers to cerebral hypoxic-ischemic injury caused by asphyxia during perinatal period, which is one of the important causes of neonatal death and sequelae. Early and accurate diagnosis of HIE is of great significance for the prognostic evaluation of patients. The purpose of this study is to explore the efficacy of diffusion-kurtosis imaging (DKI) and diffusion-weighted imaging (DWI) in the diagnosis of early HIE. METHODS: Twenty Yorkshire newborn piglets (3-5 days) were randomly divided into control group and experimental group. DWI and DKI scanning were performed at timepoints of 3, 6, 9, 12, 16, and 24 h after hypoxic-ischemic exposure. At each timepoint, the parameter values obtained by each group scan were measured, and the lesion area of the apparent diffusion coefficient (ADC) map and mean diffusion coefficient (MDC) map were measured. (For better interpretation of this study, we replaced the description of MD with MDC). Then, we completely removed the brain for pathological examination, and observed the state of cells and mitochondria in the ADC/MDC matching area (the actual area of the lesion), and the mismatch area (the area around the lesion). RESULTS: In the experimental group, the ADC and MDC values decreased with time, but the MDC decreased more significantly and the change rate was higher. Both MDC and ADC values changed rapidly from 3 to 12 h and slowly from 12 to 24 h. The MDC and ADC images showed obvious lesions at 3 h for the first time. At this time, the area of ADC lesions was larger than that of MDC. As the lesions developed, the area of ADC maps was always larger than that of the MDC maps within 24 h. By observing the microstructure of the tissues by light microscopy, we found that the ADC and MDC matching area in the experimental group showed swelling of neurons, infiltration of inflammatory cells, and local necrotic lesions. Consistent with the observation under light microscope, pathological changes were observed in the matching ADC and MDC regions under electron microscopy as well, including collapse of mitochondrial membrane, fracture of partial mitochondrial ridge, and emergence of autophagosomes. In the mismatching region, the above pathological changes were not observed in the corresponding region of the ADC map. CONCLUSIONS: DKI's characteristic parameter MDC is better than ADC (parameter of DWI) to reflect the real area of the lesion. Therefore, DKI is superior to DWI in diagnosing early HIE.

Tissue perfusion of the kurtosis/diffusion mismatch differs from the central core and peripheral regions in acute cerebral infarction patients.

BACKGROUND: Despite its wide adoption in stroke imaging, the diffusion-weighted imaging (DWI) lesion is heterogeneous. The emerging diffusion kurtosis imaging (DKI) has been postulated to resolve the graded DWI lesion. PURPOSE: To determine the perfusion characteristics of the central infarction core, kurtosis/diffusion mismatch, and peripheral regions. MATERIAL AND METHODS: Patients with acute ischemic stroke underwent DWI, DKI, and perfusion-weighted imaging (PWI) scans. The patients were divided into mean kurtosis (MK)/mean diffusivity (MD) match and mismatch groups. Perfusion parameters were measured in the MK/MD lesion and peripheral areas in the MK/MD match group. We also analyzed perfusion status in the MK/MD lesion mismatch area for the mismatch group. RESULTS: A total of 40 eligible patients (24 MK/MD match and 16 MK/MD mismatch) were enrolled in the final data analysis. The MTT and TTP progressively decreased, while the cerebral blood flow (CBF) and cerebral blood volume (CBV) increased from the central to peripheral areas. In addition, CBF in the MK/MD mismatch region was significantly higher than that in the central region (P < 0.05), but similar to the peripheral region. Furthermore, CBV in the MK/MD mismatch region did not differ significantly from that of the central region, but both were significantly lower than that of the peripheral area (P < 0.05). CONCLUSION: The MK/MD mismatch region had blood flow similar to the peripheral region but with a reduced blood volume, indicating that it was less ischemic from the infarction core, albeit insufficient collateral circulation.

Automated Quantification of Brain Lesion Volume From Post-trauma MR Diffusion-Weighted Images.

Objectives: Determining the volume of brain lesions after trauma is challenging. Manual delineation is observer-dependent and time-consuming and cannot therefore be used in routine practice. The study aimed to evaluate the feasibility of an automated atlas-based quantification procedure (AQP) based on the detection of abnormal mean diffusivity (MD) values computed from diffusion-weighted MR images. Methods: The performance of AQP was measured against manual delineation consensus by independent raters in two series of experiments based on: (i) realistic trauma phantoms (n = 5) where low and high MD values were assigned to healthy brain images according to the intensity, form and location of lesion observed in real TBI cases; (ii) severe TBI patients (n = 12 patients) who underwent MR imaging within 10 days after injury. Results: In realistic TBI phantoms, no statistical differences in Dice similarity coefficient, precision and brain lesion volumes were found between AQP, the rater consensus and the ground truth lesion delineations. Similar findings were obtained when comparing AQP and manual annotations for TBI patients. The intra-class correlation coefficient between AQP and manual delineation was 0.70 in realistic phantoms and 0.92 in TBI patients. The volume of brain lesions detected in TBI patients was 59 ml (19-84 ml) (median; 25-75th centiles). Conclusions: Our results support the feasibility of using an automated quantification procedure to determine, with similar accuracy to manual delineation, the volume of low and high MD brain lesions after trauma, and thus allow the determination of the type and volume of edematous brain lesions. This approach had comparable performance with manual delineation by a panel of experts. It will be tested in a large cohort of patients enrolled in the multicenter OxyTC trial (NCT02754063).

Effects of Coformer and Polymer on Particle Surface Solution-Mediated Phase Transformation of Cocrystals in Aqueous Media.

The purpose of the present study was to investigate the effect of the coformer difference on particle surface solution-mediated phase transformation (PS-SMPT) during cocrystal particle dissolution in aqueous media in the absence and presence of polymers. SMPT can occur either in the bulk phase or at the particle surface because drug molecules can be supersaturated at the dissolving cocrystal surface, as well as in the bulk phase. Previously, bulk phase SMPT has been primarily investigated in formulation development. However, little is known about the effects of coformers and polymers on PS-SMPT of cocrystals. In this study, six carbamazepine (CBZ) cocrystals were used as model cocrystals (malonic acid (MAL), succinic acid (SUC), glutaric acid (GLA), adipic acid (ADP), saccharin (SAC), and nicotinamide (NCT); nonsink dissolution tests were performed with or without a precipitation inhibitor (hydroxypropyl methylcellulose (HPMC)) at pH 6.5. The residual particles were analyzed by powder X-ray diffraction, differential scanning calorimetry, polarized light microscopy (PLM), and scanning electron microscopy. Real-time PLM was used to directly observe rapid PS-SMPT. In the absence of HPMC, supersaturation was not observed in the bulk phase for all cocrystals. All cocrystals rapidly transformed to CBZ dihydrate aggregates via PS-SMPT (mostly within 1 min). In contrast, in the presence of 0.1% HPMC, supersaturation was observed for CBZ-SUC, CBZ-ADP, CBZ-SAC, and CBZ-NCT but not for CBZ-MAL and CBZ-GLA. The cocrystals with lower solubility coformers tended to induce higher supersaturation in the bulk phase. The PS-SMPT of CBZ-SUC, CBZ-ADP, and CBZ-SAC was slowed down by HPMC. By suppressing PS-SMPT, the cocrystals exhibited its supersaturation potential, depending on the properties of each coformer. To take advantage of the supersaturation potential of cocrystals to improve oral drug absorption, it is important to suppress particle surface SMPT in addition to bulk phase SMPT.

Volumetric and microstructural regional changes of the hippocampus underlying development of recall performance after extended retention intervals.

Performance on recall tests improves through childhood and adolescence, in part due to structural maturation of the medial temporal cortex. Although partly different processes support successful recall over shorter vs. longer intervals, recall is usually tested after less than an hour. The aim of the present study was to test whether there are unique developmental changes in recall performance using extended retention intervals, and whether these are related to structural maturation of sub-regions of the hippocampus. 650 children and adolescents from 4.1 to 24.8 years were assessed in total 962 times (mean interval ≈ 1.8 years). The California Verbal Learning Test (CVLT) and the Rey Complex Figure Test (CFT) were used. Recall was tested 30 min and ≈ 10 days after encoding. We found unique developmental effects on recall in the extended retention interval condition independently of 30 min recall performance. For CVLT, major improvements happened between 10 and 15 years. For CFT, improvement was linear and was accounted for by visuo-constructive abilities. The relationships did not show anterior-posterior hippocampal axis differences. In conclusion, performance on recall tests using extended retention intervals shows unique development, likely due to changes in encoding depth or efficacy, or improvements of long-term consolidation processes.

Differentiating between Alzheimer's disease, amnestic mild cognitive impairment, and normal aging via diffusion kurtosis imaging.

Diffusion kurtosis imaging can be used to assess pathophysiological changes in tissue structure and to diagnose central nervous system diseases. However, its sensitivity in assessing hippocampal differences between patients with Alzheimer's disease and those with amnestic mild cognitive impairment has not been characterized. Here, we examined 20 individuals with Alzheimer's disease (11 men and 9 women, mean 73.2 ± 4.49 years), 20 with amnestic mild cognitive impairment (10 men and 10 women, mean 71.55 ± 4.77 years), and 20 normal controls (11 men and 9 women, mean 70.45 ± 5.04 years). We conducted diffusion kurtosis imaging, using a 3.0 T magnetic resonance scanner, to compare hippocampal differences among the three groups. The results demonstrated that the right hippocampal volume and bilateral mean kurtosis were remarkably smaller in individuals with Alzheimer's disease compared with those with amnestic mild cognitive impairment and normal controls. Further, the mean kurtosis was lower in the amnestic mild cognitive impairment group compared with the normal control group. The mean diffusion in the left hippocampus was lower in the Alzheimer's disease group than in the amnestic mild cognitive impairment and normal control groups, while the mean diffusion in the right hippocampus was lower in the Alzheimer's disease group than in the normal control group. Fractional anisotropy was similar among the three groups. These results verify that bilateral mean kurtosis and mean diffusion are sensitive to the diagnosis of Alzheimer's disease and amnestic mild cognitive impairment. This study was approved by the Ethics Review Board of Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, China on May 4, 2010 (approval No. 2010(C)-6).

Investigation of Neurodegenerative Processes in Amyotrophic Lateral Sclerosis Using White Matter Fiber Density.

In the current work two novel parameters, fiber density (FD) and mean diffusion signal (MDS) are investigated for evaluating neurodegenerative processes in amyotrophic lateral sclerosis (ALS). The MDS provides a measure of the FD but is derived directly from the diffusion signal. Using tract-based spatial statistics (TBSS), pathological changes across the entire white matter and changes in the parameters over time were evaluated. The results were related to those obtained using the fractional anisotropy (FA) value. A widespread pattern of significantly decreased FD and MDS values was observed. A strong trend towards statistical significance was seen in similar white matter structures using TBSS analysis based on the FA value. Longitudinal analysis of the FD values demonstrated continuing deterioration of the same fiber tracts that were shown to be impaired in the group analysis. The findings suggest that MDS and in particular FD show great promise for evaluating microstructural white matter changes in ALS and may be more sensitive than the more commonly used FA value.

Experimental study of diffusion kurtosis imaging in predicting radiotherapy sensitivity of esophageal carcinoma / 中华放射医学与防护杂志

Objective To explore the value of diffusion kurtosis imaging (DKI) in predicting radiotherapy sensitivity of esophageal cancer from the animal model level.Methods BALB/c nude mice were subcutaneously injected with Eca-109 cell lines to form xenograft tumors.The tumors received a single dose of 15 Gy (6 MV X-rays) in the experimental group or had no any treatment as control.The volume of transplanted tumor,the change of ADC,MK and MD values,and the tumor cell density and necrosis ratio of these two groups were observed at the corresponding time points.Results The growth of xenograft volume in the experimental group was suppressed and it was significantly smaller than that in the control group (t=3.206-6.149,P＜0.05) at the 7th day after radiotherapy.From the 3rd day after radiotherapy,the ADC and MD values of the experimental group were significantly higher than those of the control group,and the MK values was lower than those in the control group (tADC =-11.018--2.049,tMD =-6.609--2.052,tMK =2.492-9.323,P＜0.05).Meanwhile,the tumor cell density of the control group was higher than that of the experimental group,and the proportion of necrosis in the experimental group was higher than that in the control group (tdensity =-8.387--2.239,t is =2.980-17.430,P＜0.05).Conclusions A single large dose radiation could inhibit the growth of xenograft.ADC,MK,MD values changed at the early stage prior to morphological changes of tumor in consistent with the change of cell density and necrosis ratio.DKI has the potential value in predicting radiotherapy sensitivity of esophageal carcinoma.

Intravoxel incoherent motion (IVIM) and non-Gaussian diffusion MRI of the lactating breast.

PURPOSE: To investigate the effect of breastfeeding on IVIM and non-Gaussian diffusion MRI in the breast. MATERIALS AND METHODS: An IRB approved prospective study enrolled seventeen volunteers (12 in lactation and 5 with post-weaning, range 31-43 years; mean 35.4 years). IVIM (fIVIM and D*) and non-Gaussian diffusion (ADC0 and K) parameters using 16 b values, plus synthetic apparent diffusion coefficients (sADCs) from 2 key b values (b = 200 and 1500 s/mm2) were calculated using regions of interest. ADC0 maps of the whole breast were generated and their contrast patterns were evaluated by two independent readers using retroareolar and segmental semi-quantitative scores. To compare the diffusion and IVIM parameters, Wilcoxon signed rank tests were used between pre- and post-breastfeeding and Mann-Whitney tests were used between post-weaning and pre- or post-breastfeeding. RESULTS: ADC0 and sADC values significantly decreased post-breastfeeding (1.90 vs. 1.72 × 10-3 mm2/s, P < 0.001 and 1.39 vs. 1.25 × 10-3 mm2/s, P < 0.001) while K values significantly increased (0.33 vs. 0.44, P < 0.05). fIVIM values significantly increased after breastfeeding (1.97 vs. 2.97%, P < 0.01). No significant difference was found in D* values. There was significant heterogeneity in ADC0 maps post-breastfeeding, both in retroareolar and segmental scores (P < 0.0001 and =0.0001). CONCLUSION: IVIM and non-Gaussian diffusion parameters significantly changed between pre- and post-breastfeeding status, and care needs to be taken in interpreting diffusion-weighted imaging (DWI) data in lactating breasts.

Diffusion characteristics of the fornix in patients with Alzheimer's disease.

White matter degradation is a major part of the pathogenesis of Alzheimer's disease (AD). The fornix is the predominant outflow tract from the hippocampus, and alterations to its microstructure in patients with AD are still being explored. Diffusion tensor imaging (DTI) is an in vivo neuroimaging technique that can provide unique information about alterations in tissue microstructure, which can indicate underlying neurobiological process at the microstructural level. In this prospective study, DTI was used to assess and analyze the microstructural features of the fornix in subjects with AD (n = 17), mild cognitive impairment (MCI; n = 12) and healthy controls (n = 17). DTI was performed using Explore DTI software and the FSL package. Within the fornix, patients with AD showed decreased fractional anisotropy values and length of fiber tracts of the fornix relative to healthy controls, but higher mean diffusivity values. MCI subjects showed a trend towards elevated mean diffusivity values in the fornix. The data suggest that DTI provides supporting information on the microstructural alteration of the fornix in patients with AD, and that these diffusion characteristics of the fornix may be helpful for the clinical diagnosis of AD.

Comparison of image sensitivity between conventional tensor-based and fast diffusion kurtosis imaging protocols in a rodent model of acute ischemic stroke.

Diffusion kurtosis imaging (DKI) can offer a useful complementary tool to routine diffusion MRI for improved stratification of heterogeneous tissue damage in acute ischemic stroke. However, its relatively long imaging time has hampered its clinical application in the emergency setting. A recently proposed fast DKI approach substantially shortens the imaging time, which may help to overcome the scan time limitation. However, to date, the sensitivity of the fast DKI protocol for the imaging of acute stroke has not been fully described. In this study, we performed routine and fast DKI scans in a rodent model of acute stroke, and compared the sensitivity of diffusivity and kurtosis indices (i.e. axial, radial and mean) in depicting acute ischemic lesions. In addition, we analyzed the contrast-to-noise ratio (CNR) between the ipsilateral ischemic and contralateral normal regions using both conventional and fast DKI methods. We found that the mean kurtosis shows a relative change of 47.1 ± 7.3% between the ischemic and contralateral normal regions, being the most sensitive parameter in revealing acute ischemic injury. The two DKI methods yielded highly correlated diffusivity and kurtosis measures and lesion volumes (R(2) ⩾ 0.90, p < 0.01). Importantly, the fast DKI method exhibited significantly higher CNR of mean kurtosis (1.6 ± 0.2) compared with the routine tensor protocol (1.3 ± 0.2, p < 0.05), with its CNR per unit time (CNR efficiency) approximately doubled when the scan time was taken into account. In conclusion, the fast DKI method provides excellent sensitivity and efficiency to image acute ischemic tissue damage, which is essential for image-guided and individualized stroke treatment.

Validation of fast diffusion kurtosis MRI for imaging acute ischemia in a rodent model of stroke.

Diffusion-weighted imaging (DWI) captures ischemic tissue that is likely to infarct, and has become one of the most widely used acute stroke imaging techniques. Diffusion kurtosis imaging (DKI) has lately been postulated as a complementary MRI method to stratify the heterogeneously damaged DWI lesion. However, the conventional DKI acquisition time is relatively long, limiting its use in the acute stroke setting. Recently, a fast kurtosis mapping method has been demonstrated in fixed brains and control subjects. The fast DKI approach provides mean diffusion and kurtosis measurements under substantially reduced scan time, making it amenable to acute stroke imaging. Because it is not practical to obtain and compare different means of DKI to test whether the fast DKI method can reliably detect diffusion and kurtosis lesions in acute stroke patients, our study investigated its diagnostic value using an animal model of acute stroke, a critical step before fast DKI acquisition can be routinely applied in the acute stroke setting. We found significant correlation, per voxel, between the diffusion and kurtosis coefficients measured using the fast and conventional DKI protocols. In acute stroke rats, the two DKI methods yielded diffusion and kurtosis lesions that were in good agreement. Importantly, substantial kurtosis-diffusion lesion mismatch was observed using the conventional (26 ± 13%, P < 0.01) and fast DKI methods (23 ± 8%, P < 0.01). In addition, regression analysis showed that the kurtosis-diffusion lesion mismatches obtained using conventional and fast DKI methods were substantially correlated (R(2) = 0.57, P = 0.02). Our results confirmed that the recently proposed fast DKI method is capable of capturing heterogeneous diffusion and kurtosis lesions in acute ischemic stroke, and thus is suitable for translational applications in the acute stroke clinical setting.