Diffusion-weighted Imaging Measures Research Articles

Design and methodology for a proof of mechanism study of individualized neuronavigated continuous Theta burst stimulation for auditory processing in adolescents with autism spectrum disorder.

It has been suggested that aberrant excitation/inhibition (E/I) balance and dysfunctional structure and function of relevant brain networks may underlie the symptoms of autism spectrum disorder (ASD). However, the nomological network linking these constructs to quantifiable measures and mechanistically relating these constructs to behavioral symptoms of ASD is lacking. Herein we describe a within-subject, controlled, proof-of-mechanism study investigating the pathophysiology of auditory/language processing in adolescents with ASD. We utilize neurophysiological and neuroimaging techniques including magnetic resonance spectroscopy (MRS), diffusion-weighted imaging (DWI), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG) metrics of language network structure and function. Additionally, we apply a single, individually targeted session of continuous theta burst stimulation (cTBS) as an experimental probe of the impact of perturbation of the system on these neurophysiological and neuroimaging outcomes. MRS, fMRI, and MEG measures are evaluated at baseline and immediately prior to and following cTBS over the posterior superior temporal cortex (pSTC), a region involved in auditory and language processing deficits in ASD. Also, behavioral measures of ASD and language processing and DWI measures of auditory/language network structures are obtained at baseline to characterize the relationship between the neuroimaging and neurophysiological measures and baseline symptom presentation. We hypothesize that local gamma-aminobutyric acid (GABA) and glutamate concentrations (measured with MRS), and structural and functional activity and network connectivity (measured with DWI and fMRI), will significantly predict MEG indices of auditory/language processing and behavioral deficits in ASD. Furthermore, a single session of cTBS over left pSTC is hypothesized to lead to significant, acute changes in local glutamate and GABA concentration, functional activity and network connectivity, and MEG indices of auditory/language processing. We have completed the pilot phase of the study (n=20 Healthy Volunteer adults) and have begun enrollment for the main phase with adolescents with ASD (n=86; age 14-17). If successful, this study will establish a nomological network linking local E/I balance measures to functional and structural connectivity within relevant brain networks, ultimately connecting them to ASD symptoms. Furthermore, this study will inform future therapeutic trials using cTBS to treat the symptoms of ASD.

Sodium accumulation in breast cancer predicts malignancy and treatment response

BackgroundBreast cancer remains a leading cause of death in women and novel imaging biomarkers are urgently required. Here, we demonstrate the diagnostic and treatment-monitoring potential of non-invasive sodium (23Na) MRI in preclinical models of breast cancer.MethodsFemale Rag2−/−Il2rg−/− and Balb/c mice bearing orthotopic breast tumours (MDA-MB-231, EMT6 and 4T1) underwent MRI as part of a randomised, controlled, interventional study. Tumour biology was probed using ex vivo fluorescence microscopy and electrophysiology.Results23Na MRI revealed elevated sodium concentration ([Na+]) in tumours vs non-tumour regions. Complementary proton-based diffusion-weighted imaging (DWI) linked elevated tumour [Na+] to increased cellularity. Combining 23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared with either parameter alone. Ex vivo assessment of isolated tumour slices confirmed elevated intracellular [Na+] ([Na+]i); extracellular [Na+] ([Na+]e) remained unchanged. Treatment with specific inward Na+ conductance inhibitors (cariporide, eslicarbazepine acetate) did not affect tumour [Na+]. Nonetheless, effective treatment with docetaxel reduced tumour [Na+], whereas DWI measures were unchanged.ConclusionsOrthotopic breast cancer models exhibit elevated tumour [Na+] that is driven by aberrantly elevated [Na+]i. Moreover, 23Na MRI enhances the diagnostic capability of DWI and represents a novel, non-invasive biomarker of treatment response with superior sensitivity compared to DWI alone.

Episodic Past, Future, and counterfactual thinking in Relapsing-Remitting Multiple sclerosis

Multiple sclerosis (MS) is a progressive disease characterized by widespread white matter lesions in the brain and spinal cord. In addition to well-characterized motor deficits, MS results in cognitive impairments in several domains, notably in episodic autobiographical memory. Recent studies have also revealed that patients with MS exhibit deficits in episodic future thinking, i.e., our capacity to imagine possible events that may occur in our personal future. Both episodic memory and episodic future thinking have been shown to share cognitive and neural mechanisms with a related kind of hypothetical simulation known as episodic counterfactual thinking: our capacity to imagine alternative ways in which past personal events could have occurred but did not. However, the extent to which episodic counterfactual thinking is affected in MS is still unknown. The current study sought to explore this issue by comparing performance in mental simulation tasks involving either past, future or counterfactual thoughts in relapsing-remitting MS. Diffusion weighted imaging (DWI) measures were also extracted to determine whether changes in structural pathways connecting the brain’s default mode network (DMN) would be associated with group differences in task performance. Relative to controls, patients showed marked reductions in the number of internal details across all mental simulations, but no differences in the number of external and semantic-based details. It was also found that, relative to controls, patients with relapsing-remitting MS reported reduced composition ratings for episodic simulations depicting counterfactual events, but not so for actual past or possible future episodes. Additionally, three DWI measures of white matter integrity—fractional anisotropy, radial diffusivity and streamline counts—showed reliable differences between patients with relapsing-remitting MS and matched healthy controls. Importantly, DWI measures associated with reduced white matter integrity in three association tracts on the DMN—the right superior longitudinal fasciculus, the left hippocampal portion of the cingulum and the left inferior longitudinal fasciculus—predicted reductions in the number of internal details during episodic counterfactual simulations. Taken together, these results help to illuminate impairments in episodic simulation in relapsing-remitting MS and show, for the first time, a differential association between white matter integrity and deficits in episodic counterfactual thinking in individuals with relapsing-remitting MS.

Difference in distribution functions: A new diffusion weighted imaging metric for estimating white matter integrity

Diffusion weighted imaging (DWI) is a widely recognized neuroimaging technique to evaluate the microstructure of brain white matter. The objective of this study is to establish an improved automated DWI marker for estimating white matter integrity and investigating ageing related cognitive decline. The concept of Wasserstein distance was introduced to help establish a new measure: difference in distribution functions (DDF), which captures the difference of reshaping one's mean diffusivity (MD) distribution to a reference MD distribution. This new DWI measure was developed using a population-based cohort (n=19,369) from the UK Biobank. Validation was conducted using the data drawn from two independent cohorts: the Sydney Memory and Ageing Study, a community-dwelling sample (n=402), and the Renji Cerebral Small Vessel Disease Cohort Study (RCCS), which consisted of cerebral small vessel disease (CSVD) patients (n=171) and cognitively normal controls (NC) (n=43). DDF was associated with age across all three samples and better explained the variance of changes than other established DWI measures, such as fractional anisotropy, mean diffusivity and peak width of skeletonized mean diffusivity (PSMD). Significant correlations between DDF and cognition were found in the UK Biobank cohort and the MAS cohort. Binary logistic analysis and receiver operator characteristic curve analysis of RCCS demonstrated that DDF had higher sensitivity in distinguishing CSVD patients from NC than the other DWI measures. To demonstrate the flexibility of DDF, we calculated regional DDF which also showed significant correlation with age and cognition. DDF can be used as a marker for monitoring the white matter microstructural changes and ageing related cognitive decline in the elderly.

Role of the non-invasive imaging techniques in monitoring and understanding the evolution of brain edema.

Human brain injury elicits accumulation of water within the brain due to a variety of pathophysiological processes. As our understanding of edema emerged two temporally (and cellular) distinct processes were identified, cytotoxic and vasogenic edema. The emergence of both types of edema is reflected by the temporal evolution and is influenced by the underlying pathology (type and extent). However, this two-edema compartment model does not adequately describe the transition between cytotoxic and vasogenic edema. Hence, a third category has been proposed, termed ionic edema, that is observed in the transition between cytotoxic and vasogenic edema. Magnetic resonance neuroimaging of edema today primarily utilizes T2-weighted (T2WI) and diffusion-weighted imaging (DWI). Clinical diagnostics and translational science studies have clearly demonstrated the temporal ability of both T2WI and DWI to monitor edema content and evolution. DWI measures water mobility within the brain reflecting cytotoxic edema. T2WI at later time points when vasogenic edema develops visualizes increased water content in the brain. Clinically relevant imaging modalities, including ultrasound and positron emission tomography, are not typically used to assess edema. In sum, edema imaging is an important cornerstone of clinical diagnostics and translational studies and can guide effective therapeutics manage edema and improve patient outcomes.

Relationships between spinal cord blood flow measured with flow-sensitive alternating inversion recovery (FAIR) and neurobehavioral outcomes in rat spinal cord injury

In the traumatically injured spinal cord, decreased perfusion is believed to contribute to secondary tissue damage beyond the primary mechanical impact, and restoration of perfusion is believed to be a promising therapeutic target. However, methods to monitor spinal cord perfusion non-invasively are limited. Perfusion magnetic resonance imaging (MRI) techniques established for the brain have not been routinely adopted to the spinal cord. The purpose of this study was to examine the relationship between spinal cord blood flow (SCBF) and injury severity in a rat thoracic spinal cord contusion injury (SCI) model using flow-sensitive alternating inversion recovery (FAIR) with two variants of the label position. SCBF as a marker of severity was compared to T1 mapping and to spinal cord-optimized diffusion weighted imaging (DWI) with filtered parallel apparent diffusion coefficient. Thirty-eight rats underwent a T10 contusion injury with varying severities (8 sham; 10 mild; 10 moderate; 10 severe) with MRI performed at 1 day post injury at the lesion site and follow-up neurological assessments using the Basso, Beattie, Bresnahan (BBB) locomotor scoring up to 28 days post injury. Using whole-cord regions of interest at the lesion epicenter, SCBF was decreased with injury severity and had a significant correlation with BBB scores at 28 days post injury. Importantly, estimates of arterial transit times (ATT) in the injured spinal cord were not altered after injury, which suggests that FAIR protocols optimized to measure SCBF provide more value in the context of acute traumatic injury to the cord. T1-relaxation time constants were strongly related to injury severity and had a larger extent of changes than either SCBF or DWI measures. These findings suggest that perfusion decreases in the spinal cord can be monitored non-invasively after injury, and multi-parametric MRI assessments of perfusion, diffusion, and relaxation capture unique features of the pathophysiology of preclinical injury.

Diffusion MRI abnormalities in adolescent rats given repeated mild traumatic brain injury.

ObjectiveMild traumatic brain injury (mTBI) is a serious health concern in the adolescent population. Repeated mTBI may result in more pronounced deficits, and has been associated with long‐term neurological consequences including neurodegeneration. As such, there is a critical need for the development of objective mTBI biomarkers to help guide medical management. Diffusion‐weighted imaging (DWI) is an advanced magnetic resonance imaging (MRI) technique that may detect brain abnormalities after mTBI. Diffusion tensor imaging (DTI) is the most commonly applied DWI method, and initial studies have reported DTI changes in mTBI patients. Furthermore, new DWI methods (e.g., track‐weighted imaging; TWI) are being developed that may also be sensitive to mTBIs, but remain to be comprehensively studied.MethodsThis study utilized the Awake Closed Head Injury (ACHI) model of mTBI to investigate changes in DTI and TWI following repeated mTBI in adolescent male and female rats. A total of four ACHI impacts, two/day over two consecutive days, were delivered beginning on postnatal day 25. At 1 day and 7 days postinjury, rats were euthanized and brains were collected for DWI analyses.ResultsRats given repeated mTBI displayed changes in fractional anisotropy and radial diffusivity (i.e., DTI measures), as well as track density (i.e., TWI).InterpretationThese findings are consistent with initial DTI findings in mTBI patients, suggest that TWI may complement DTI, support the utility of DWI measures as biomarkers in mTBI, and further validate the ACHI rat model of mTBI.

M16 - Epigenetic Age Acceleration Assessed In White-Matter Integrity: Towards A Biomarker of Successfully Brain Aging

Background Biological age acceleration as measured by aggregate epigenetic markers has been associated with a number of phenotypes including Parkinson’s, obesity and physical fitness in the elderly. Additionally, epigenetic indices of age acceleration are touted as molecular biomarkers of brain aging, based on findings linking epigenetic age of prefrontal cortex tissue with Alzheimer’s-related phenotypes. Yet, in order to develop a clinically useful brain age acceleration biomarker, peripheral tissue, rather than neural tissue, is preferable. Likewise, in vivo neuroimaging measures are desirable. To that end, we examined the relationship between blood-derived epigenetic measures of age acceleration and white matter integrity, as indexed with diffusion weighted imaging (DWI), in a large randomly ascertained family cohort. Our goal was to investigate processes that underlie inter-individual variability in age-related changes in the white matter tracts. DWI measures of white mater integrity are among the most sensitive imaging measures of aging with demonstrated heritabilities. Methods Using blood DNA methylation data taken from a Mexican-American extended pedigree sample (n=634; mean age=49.16y, range 28.11y-97.52y), epigenetic age was estimated using the method developed by S. Horvath (2013). Epigenetic age acceleration was calculated as epigenetic age regressed upon age, sex, age x sex, age2, age2 x sex, and blood cell count estimates. 379 of these individuals had available DWI scans collected on a Siemens 3T Trio MRI located at the Research Imaging Institute, UTHSCSA. An average fractional anisotropy (FA) map was derived for each subject and skeletonized using the TBSS algorithm, providing FA measures for each of 16 white matter tracts and a global index. Variance decomposition methods were then used to investigate the interrelationship between epigenetic age acceleration and white matter integrity and identify genetic influences on these two phenotypes. Results Consistent with previous reports, both epigenetic age acceleration and white matter integrity measures are heritable in this sample. We observe significant (FDR Discussion Here we demonstrate that age acceleration, as measured via methylation profiles from peripheral blood, is significantly correlated with white matter integrity in a number of tracts within the brain. We also demonstrate evidence of shared genetic influences acting on both age acceleration and white matter integrity. These findings provide an interesting window into the neurobiology of aging processes within the brain and a potential new biomarker of normal and pathological brain aging.

Detection of acute nervous system injury with advanced diffusion-weighted MRI: a simulation and sensitivity analysis.

Diffusion-weighted imaging (DWI) is a powerful tool to investigate the microscopic structure of the central nervous system (CNS). Diffusion tensor imaging (DTI), a common model of the DWI signal, has a demonstrated sensitivity to detect microscopic changes as a result of injury or disease. However, DTI and other similar models have inherent limitations that reduce their specificity for certain pathological features, particularly in tissues with complex fiber arrangements. Methods such as double pulsed field gradient (dPFG) and q-vector magic angle spinning (qMAS) have been proposed to specifically probe the underlying microscopic anisotropy without interference from the macroscopic tissue organization. This is particularly important for the study of acute injury, where abrupt changes in the microscopic morphology of axons and dendrites manifest as focal enlargements known as beading. The purpose of this work was to assess the relative sensitivity of DWI measures to beading in the context of macroscopic fiber organization and edema. Computational simulations of DWI experiments in normal and beaded axons demonstrated that, although DWI models can be highly specific for the simulated pathologies of beading and volume fraction changes in coherent fiber pathways, their sensitivity to a single idealized pathology is considerably reduced in crossing and dispersed fibers. However, dPFG and qMAS have a high sensitivity for beading, even in complex fiber tracts. Moreover, in tissues with coherent arrangements, such as the spinal cord or nerve fibers in which tract orientation is known a priori, a specific dPFG sequence variant decreases the effects of edema and improves specificity for beading. Collectively, the simulation results demonstrate that advanced DWI methods, particularly those which sample diffusion along multiple directions within a single acquisition, have improved sensitivity to acute axonal injury over conventional DTI metrics and hold promise for more informative clinical diagnostic use in CNS injury evaluation.

Callosal Function in Pediatric Traumatic Brain Injury Linked to Disrupted White Matter Integrity.

Traumatic brain injury (TBI) is the primary cause of death and disability in children and adolescents. There is considerable heterogeneity in postinjury outcome, which is only partially explained by injury severity. Imaging biomarkers may help explain some of this variance, as diffusion weighted imaging is sensitive to the white matter disruption that is common after injury. The corpus callosum (CC) is one of the most commonly reported areas of disruption. In this multimodal study, we discovered a divergence within our pediatric moderate-to-severe TBI sample 1-5 months postinjury. A subset of the TBI sample showed significant impairment in CC function, which is supported by additional results showing deficits in CC structural integrity. This subset also had poorer neurocognitive functioning. Our research sheds light on postinjury heterogeneity.

Optimization of b‐value sampling for diffusion‐weighted imaging of the kidney

Diffusion-weighted imaging (DWI) involves data acquisitions at multiple b values. In this paper, we presented a method of selecting the b values that maximize estimation precision of the biexponential analysis of renal DWI data. We developed an error propagation factor for the biexponential model, and proposed to optimize the b-value samplings by minimizing the error propagation factor. A prospective study of four healthy human subjects (eight kidneys) was done to verify the feasibility of the proposed protocol and to assess the validity of predicted precision for DWI measures, followed by Monte Carlo simulations of DWI signals based on acquired data from renal lesions of 16 subjects. In healthy subjects, the proposed methods improved precision (P = 0.003) and accuracy (P < 0.001) significantly in region-of-interest based biexponential analysis. In Monte Carlo simulation of renal lesions, the b-sampling optimization lowered estimation error by at least 20-30% compared with uniformly distributed b values, and improved the differentiation between malignant and benign lesions significantly. In conclusion, the proposed method has the potential of maximizing the precision and accuracy of the biexponential analysis of renal DWI.

Quantitative diffusion weighted imaging measures in patients with multiple sclerosis

Diffusion-weighted imaging (DWI) has been proposed as a sensitive measure of disease severity capable of detecting subtle changes in gray matter and white matter brain compartments in patients with multiple sclerosis (MS). However, DWI has been applied to the study of MS clinical subtypes in only a few studies. The objective of this study was to demonstrate the validity of a novel, fully automated method for the calculation of quantitative DWI measures. We also wanted to assess the correlation between whole brain (WB)-DWI variables and clinical and MRI measures of disease severity in a large cohort of MS patients. For this purpose we studied 432 consecutive MS patients (mean age 44.4±10.2 years), 16 patients with clinically isolated syndrome (CIS) and 38 normal controls (NC) using 1.5 T brain MRI. Clinical disease subtypes were as follows: 294 relapsing–remitting (RR), 123 secondary-progressive (SP) and 15 primary-progressive (PP). Mean disease duration was 12±10 years. Mean Expanded Disability Status Scale (EDSS) was 3.3±2.1. Brain parenchymal fraction (BPF), gray matter fraction (GMF) and white matter fraction (WMF) were calculated using a fully automated method. Mean parenchymal diffusivity (MPD) maps were created. DWI indices of peak position (PP), peak height (PH), MPD and entropy (ENT) were obtained. T2- and T1-lesion volumes (LV), EDSS, ambulation index (AI) and nine-hole peg test (9-HPT) were also assessed. MS patients had significantly lower BPF (d=1.26; p<0.001) and GMF (d=0.61; p=0.003), and higher ENT (d=1.2; p<0.0001), MPD (d=1.04; p<0.0001) and PH (d=0.47; p=0.045) than NC subjects. A GLM analysis, adjusted for age and multiple comparisons, revealed significant differences between different clinical subtypes for BPF, GMF, ENT, PH, PP, T2-LV and T1-LV (p<0.0001), WMF (p=0.001) and MPD (p=0.023). In RR and SP MS patients, ENT showed a more robust correlation with other MRI (r=0.54 to 0.67, p<0.0001) and clinical (r=0.31 to 0.36, p<0.0001) variables than MPD (r=0.23 to 0.41, p<0.001 for MRI and r=0.13 to 0.18; p=0.006 to p<0.001 for clinical variables). The GMF and BPF showed a slightly stronger relationship with all clinical variables (r=0.33 to 0.48; p<0.0001), when compared to both lesion and DWI measures. ENT (R2=0.28; p<0.0001) and GMF (R2=0.26; p<0.001) were best related with SP disease course. This study highlights the validity of DWI in discerning differences between NC and MS patients, as well as between different MS subtypes. ENT is a sensitive marker of overall brain damage that is strongly related to clinical impairment in patients with SP MS.

The Use of PWI and DWI Measures in the Design of “Proof‐of‐Concept” Stroke Trials

The authors used serial magnetic resonance perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) to determine whether major reperfusion and the attenuation of infarct expansion are associated with improved stroke outcome. Forty-nine patients were studied with serial magnetic resonance imaging within 6 hours of stroke onset and again at 4 days (subacute studies) and 3 months (outcome studies). Two imaging parameters were examined: infarct expansion between acute and outcome studies and major reperfusion between acute and subacute studies. Patients with major reperfusion (45% of those with acute PWI lesions) were more likely to have little or no disability at outcome (National Institutes of Health Stroke Scale [NIHSS] score < or = 4, P = .0176; Barthel Index [BI] score > or = 90, P = .0547) after adjustment for baseline differences. In contrast, patients with infarct expansion (48%) were more likely to be dead or dependent at outcome (BI < 90, P = .0414; NIHSS score P = .082; modified Rankin Scale score > 2, P < .0001). These measures were used to generate sample size calculations based on hypothetical treatment effects. Therapies postulated to double the proportion of patients with major reperfusion from one third to two thirds would require 41 patients in each group (treated and untreated) to be sufficiently powered to show a difference. Interventions postulated to halve the number of patients with infarct expansion from 50% to 25% would require 66 patients in each group to show a difference. Infarct expansion and major reperfusion are associated with clinically meaningful changes in stroke outcome. These measures could be used as surrogate markers of outcome in late phase II proof-of-concept stroke studies designed to provide efficacy signals before embarking on large phase III studies with definitive clinical endpoints.