High-resolution Diffusion Tensor Imaging Research Articles

Abstract 4121198: Structural Network Alterations After Cardiopulmonary Bypass In a Juvenile Porcine Model

Background: Cardiopulmonary bypass (CPB) can trigger inflammatory and oxidative stresses in the developing brain. Clinical studies showed altered brain network structure in children after infant cardiac surgery. However, the impact of CPB on structural connectivity remains poorly understood. This study aims to determine the effects of CPB on structural connectivity and underlying cellular events using a juvenile porcine model. Methods: CPB (150 min total) was performed on 2-week-old Yorkshire piglets. High-resolution diffusion tensor imaging (DTI) and neurite orientation dispersion and density (NODDI) imaging were performed 4 weeks post-CPB in a total of 12 animals (Control; n=7, CPB; n=5). Structural connectivity assay together with histological analysis was conducted to assess the brain network organization. Results: Our network analysis (Image 1) revealed a CPB-induced reduction of structural connections in particular nodes, such as in the anterior prefrontal cortex (APC), primary somatosensory cortex, substantia nigra (SN), and globus pallidus (GP). In contrast, there was an increase in the premotor cortex (PreMC), primary motor cortex (PriMC), dorsal posterior cingulate cortex (DPCC), and somatosensory cortex (SAC). Three-dimensional images were generated based on these altered nodes, and tractography was generated to indicate changed fiber tracking (Image 2). We found reduced network connections between the basal ganglia and frontal cortex, and increased connections between the motor and posterior region. DTI and NODDI indicated that microstructures of the superior corona radiata (SCR), internal capsule (PLIC), and anterior prefrontal (AP-WM), motor (PreM-/PriM-WM), and somatosensory white matter (SA-WM) were significantly altered after CPB (Image 3). While Iba1+ microglia was activated across all brain regions after CPB (P<.05), CPB-induced oligodendrocyte immatureness was identified in the WMs involved in APC-SN and APC-GP pathways (P<.05). Notably, CPB increased the number of mature oligodendrocytes in motor and SA-WMs (P<.05) where structural connections were increased after CPB. In addition, we found SN dopaminergic neuron injury after CPB (P<.05). Conclusion: CPB altered structural network organization in the developing brain. Spatial differences in oligodendrocyte responses and susceptibility of specific subpopulations of neurons may contribute to the unique connectivity alterations observed after CPB.

Diffusion Tensor Imaging in Boys With Adrenoleukodystrophy: Identification of Cerebral Disease and Association With Neurocognitive Outcomes.

Childhood cerebral adrenoleukodystrophy (C-ALD) is a severe inflammatory demyelinating disease that must be treated at an early stage to prevent permanent brain injury and neurocognitive decline. In standard clinical practice, C-ALD lesions are detected and characterized by a neuroradiologist reviewing anatomical MRI scans. We aimed to assess whether diffusion tensor imaging (DTI) is sensitive to the presence and severity of C-ALD lesions and to investigate associations with neurocognitive outcomes after hematopoietic cell therapy (HCT). In this retrospective cohort study, we analyzed high-resolution anatomical MRI, DTI, and neurocognitive assessments from boys with C-ALD undergoing HCT at the University of Minnesota between 2011 and 2021. Longitudinal DTI data were compared with an age-matched group of boys with ALD and no lesion (NL-ALD). DTI metrics were obtained for atlas-based regions of interest (ROIs) within 3 subdivisions of the corpus callosum (CC), corticospinal tract (CST), and total white matter (WM). Between-group baseline and slope differences in fractional anisotropy (FA) and axial (AD), radial (RD), and mean (MD) diffusivities were compared using analysis of covariance accounting for age, MRI severity (Loes score), and lesion location. Among patients with NL-ALD (n = 14), stable or increasing FA, stable AD, and stable or decreasing RD and MD were generally observed during the 1-year study period across all ROIs. In comparison, patients with mild posterior lesions (Loes 1-2; n = 13) demonstrated lower baseline FA in the CC splenium (C-ALD 0.50 ± 0.08 vs NL-ALD 0.58 ± 0.04; pBH = 0.022 adjusted Benjamini-Hochberg p-value), lower baseline AD across ROIs (e.g., C-ALD 1.34 ± 0.03 ×10-9 m2/s in total WM vs NL-ALD 1.38 ± 0.04 ×10-9 m2/s; pBH = 0.005), lower baseline RD in CC body and CST, and lower baseline MD across ROIs except CC splenium. Longitudinal slopes in CC splenium showed high sensitivity and specificity in differentiating early C-ALD from NL-ALD. Among all patients with C-ALD (n = 38), baseline Loes scores and DTI metrics were associated with post-HCT neurocognitive functions, including processing speed (e.g., FA WM Spearman correlation coefficient R = 0.64) and visual-motor integration (e.g., FA WM R = 0.71). DTI was sensitive to lesion presence and severity as well as clinical neurocognitive effects of C-ALD. DTI metrics quantify C-ALD even at an early stage.

Interhemispheric Connectivity of the Human Temporal Lobes.

Interhemispheric connections of the human temporal lobes were visualized using high angular resolution diffusion tensor imaging tractography.Results are displayed on serial orthogonal sections to reveal detailed spatial relationships.Corpus callosum projections through the splenium form distinct dorsal and ventral bundles and are absent from the caudal splenium.The transcallosal pathway consists of distinct medial and lateral divisions.The results reveal projections to the external capsule and claustrum not previously described.Transcallosal and anterior commissural pathways show complex patterns of overlap and interdigitation.Surface mapping revealed areas with relatively high density of projections to the cortical surface.

Characterization of anthracycline-induced cardiotoxicity by diffusion tensor magnetic resonance imaging.

Anthracyclines are highly potent anti-cancer drugs, but their clinical use is limited by severe cardiotoxic side effects. The impact of anthracycline-induced cardiotoxicity (AIC) on left ventricular (LV) microarchitecture and diffusion properties remains unknown. This study sought to characterize AIC by cardiovascular magnetic resonance diffusion tensor imaging (DTI). Mice were treated with Doxorubicin (DOX; n = 16) for induction of AIC or saline as corresponding control (n = 15). Cardiac function was assessed via echocardiography at the end of the study period. Whole hearts (n = 8 per group) were scanned ex vivo by high-resolution DTI at 7T. Results were correlated with histopathology and mass spectrometry imaging. Mice with AIC demonstrated systolic dysfunction (LVEF 52 ± 3% vs. 43 ± 6%, P < 0.001), impaired global longitudinal strain (-19.6 ± 2.0% vs. -16.6 ± 3.0%, P < 0.01), and cardiac atrophy (LV mass index [mg/mm], 4.3 ± 0.1 vs. 3.6 ± 0.2, P < 0.01). Regional sheetlet angles were significantly lower in AIC, whereas helix angle and relative helicity remained unchanged. In AIC, fractional anisotropy was increased (0.12 ± 0.01 vs. 0.14 ± 0.02, P < 0.05). DOX-treated mice displayed higher planar and less spherical anisotropy (CPlanar 0.07 ± 0.01 vs. 0.09 ± 0.01, P < 0.01; CSpherical 0.89 ± 0.01 vs. 0.87 ± 0.02, P < 0.05). CPlanar and CSpherical yielded good discriminatory power to distinguish between mice with and without AIC (c-index 0.91 and 0.84, respectively, P for both <0.05). AIC is associated with regional changes in sheetlet angle but no major abnormalities of global LV microarchitecture. The geometric shape of the diffusion tensor is altered in AIC. DTI may provide a new tool for myocardial characterization in patients with AIC, which warrants future clinical studies to evaluate its diagnostic utility.

Neuroanatomical Correlates of Cognitive Tests in Young-onset MCI.

Mild Cognitive Impairment (MCI) is a heterogeneous condition characterised by cognitive changes that do not affect everyday functioning and may represent a predementia phase. Research on the neuroanatomical correlates of cognitive tests used to diagnose MCI is heterogeneous and has mainly focused on elderly populations of patients with MCI, usually well above the age of 65. However, the effect of ageing on brain structure is known to be substantial and to affect brain-behaviour associations in older people. We explored the brain correlates of different cognitive tests in a group of young-onset MCI (i.e., with symptoms onset before the age of 65) to minimise the effect of ageing on brain-behaviour associations. Patients with a clinical diagnosis of young-onset MCI underwent extensive cognitive assessment and multimodal Magnetic Resonance Imaging (MRI) including high-resolution T1-weighted and Diffusion Tensor Imaging (DTI) sequences. Their scores on cognitive tests were related to measures of grey matter (GM) density and white matter (WM) integrity using, respectively, Voxel Based Morphometry (VBM) and Tract-Based Spatial Statistics (TBSS). 104 young-onset MCI were recruited. VBM and TBSS whole-brain correlational analyses showed that between-subject variability in cognitive performance was significantly associated with regional variability in GM density and WM integrity. While associations between cognitive scores and focal GM density in our young-onset MCI group reflected the well-known lateralization of verbal and visuo-spatial abilities on the left and right hemispheres respectively, the associations between cognitive scores and WM microstructural integrity were widespread and diffusely involved most of the WM tracts in both hemispheres. We investigated the structural neuroanatomical correlates of cognitive tests in young-onset MCI in order to minimise the effect of ageing on brain-behaviour associations.

High resolution 0.5mm isotropic T1-weighted and diffusion tensor templates of the brain of non-demented older adults in a common space for the MIITRA atlas

High quality, high resolution T1-weighted (T1w) and diffusion tensor imaging (DTI) brain templates located in a common space can enhance the sensitivity and precision of template-based neuroimaging studies. However, such multimodal templates have not been constructed for the older adult brain. The purpose of this work which is part of the MIITRA atlas project was twofold: (A) to develop 0.5 mm isotropic resolution T1w and DTI templates that are representative of the brain of non-demented older adults and are located in the same space, using advanced multimodal template construction techniques and principles of super resolution on data from a large, diverse, community cohort of 400 non-demented older adults, and (B) to systematically compare the new templates to other standardized templates. It was demonstrated that the new MIITRA-0.5mm T1w and DTI templates are well-matched in space, exhibit good definition of brain structures, including fine structures, exhibit higher image sharpness than other standardized templates, and are free of artifacts. The MIITRA-0.5mm T1w and DTI templates allowed higher intra-modality inter-subject spatial normalization precision as well as higher inter-modality intra-subject spatial matching of older adult T1w and DTI data compared to other available templates. Consequently, MIITRA-0.5mm templates allowed detection of smaller inter-group differences for older adult data compared to other templates. The MIITRA-0.5mm templates were also shown to be most representative of the brain of non-demented older adults compared to other templates with submillimeter resolution. The new templates constructed in this work constitute two of the final products of the MIITRA atlas project and are anticipated to have important implications for the sensitivity and precision of studies on older adults.

Identifying and Re-Planning Challenging Retrospective SRS Patients to Evaluate the Potential for a White Matter Tract Sparing Knowledge-Based Planning Model

Diffusion tensor imaging (DTI) with automated tractography, along with auto-parcellation of volumetric MRI (vMRI), allows for reliable parcellation of critical white matter (WM) and hippocampal structures in the brain. Knowledge-based planning (KBP) may facilitate the optimization of new brain SRS plans that highly prioritize WM tracts and hippocampal sparing, allowing for cognitive preservation. However, building a high-performing model is challenging as the geometry of WM tracts and their proximity to planning target volumes (PTVs) can vary substantially. In this work we propose an iterative step for creating a KBP model where we used a preliminary model to identify challenging plans and worked on improving their dosimetry to refine the model predictions. Tractography of eloquent deep WM was obtained from high resolution DTI, along with auto-segmentation of bilateral hippocampi from vMRI and an open-source software for processing and analyzing brain MRI images. These ROIs were imported to the treatment planning system as organs-at-risk (OARsDTI). A preliminary KBP model was built from an IRB-approved cohort of 30 consecutive patients (75 plans total) treated for brain metastasis with non-coplanar SRS with total dose from 20 to 30 Gy in one to five fractions using a LINAC. This preliminary model was used to identify the 7 plans with the highest doses to the OARsDTI. These plans were re-optimized with new objectives on the OARsDTI that were partially or totally overlapped with the isodose line representing 30% of the prescription dose (as a surrogate for proximity to the PTV). The OARsDTI that were overlapping with the PTV were excluded from this analysis. We evaluated the re-optimized plans (PlanNew) by comparing maximum and mean dose (Dmax and Dmean, respectively) of OARsDTI to the initial values from the preliminary plans (PlanPre). In order to verify that the PlanNew were not compromising other structures or treatment goals, we also evaluated conformity index (CI), PTV coverage and the dosimetry of OARs included in the PlanPre. Additionally, the PlanNew were normalized to our clinical standard used for the PlanPre (100% of prescription dose to 98% of the PTV). In the 7 plans, there were 30 OARsDTI overlapping with the 30% isodose line. Refining the dosimetric objectives for the OARsDTI decreased the Dmean on average 31% when comparing PlanNew to Planpre (p<0.05, Wilcoxon rank-sum test). The CI of the PlanNew were not statistically different from the PlanPre. Although Dmax of PlanNew was 12% lower than Dmax of Planpre, the difference was not statistically different. The addition of a plan refinement step was shown to improve dose to the OARsDTI in 7 challenging SRS plans. The generation of these plans are a necessary step to creating a refined KBP model capable of accounting for the high variability in WM tracts geometry and their proximity with PTV.

Correlation between lenticulostriate arteries and white matter microstructure changes in patients with cerebral small vessel disease.

To explore the correlation between the number of lenticulostriate arteries (LSAs) and the white matter features in cerebral small vessel diseases (CSVD) by 3T magnetic resonance imaging (MRI). Seventy-one patients with diagnoses of CSVD were prospectively enrolled to undergo 3T MRI examination, including high-resolution vascular wall imaging (VWI) and diffusion tensor imaging (DTI). The LSAs were observed and counted on VWI, and the patients were divided into three groups according to the LSA counts. The presence of white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS) was assessed in each patient, and a composite CSVD score was calculated. Periventricular and deep white matter hyperintensity (PVWMH, DWMH) volume ratios were obtained based on automatic segmentation. Fractional anisotropy (FA) and mean diffusivity (MD) were processed by using tract-based spatial statistics (TBSS) analysis. These parameters were compared among the three groups. Correlations between the LSA counts and white matter features were also analyzed. There were differences in WMHs (P = 0.001), CMBs (P < 0.001), EPVS (P = 0.017), composite CSVD scores (P < 0.001), PVWMH volume ratios (P = 0.001), DWMH volume ratios (P < 0.001), global FA (P = 0.001), and global MD (P = 0.002) among the three groups. There were correlations between the LSA counts and WMHs (r = -0.45, P < 0.001), CMBs (r = -0.44, P < 0.001), EPVS (r = -0.28, P = 0.020), the composite CSVD score (r = -0.52, P < 0.001), DWMH volume ratio (r = -0.47, P < 0.001), PWMH volume ratio (r = -0.34, P = 0.004), global FA (r = 0.36, P = 0.002), and global MD (r = -0.33, P = 0.005). Diabetes mellitus (OR 3.36, 95% CI 1.06-10.63; P = 0.039) and increased DWMH volume ratios (OR 1.04, 95% CI 1.00-1.08; P = 0.048) were independent risk factors for a decrease in LSA counts. TBSS analysis showed differences among the three groups in global FA and MD after adjusting for age and sex (P < 0.05). The LSA counts was associated with white matter microstructure changes in CSVD and has the potential to represent the extent of subcortical microvascular damage in CSVD patients.

Sex differences in the structural rich-club connectivity in patients with Alzheimer's disease.

Alzheimer's disease (AD) is more prevalent in women than in men; however, there is a discrepancy in research on sex differences in AD. The human brain is a large-scale network with hub regions forming a central core, the rich-club, which is vital to cognitive functions. However, it is unknown whether alterations in the rich-clubs in AD differ between men and women. We aimed to investigate sex differences in the rich-club organization in the brains of patients with AD. In total, 260 cognitively unimpaired individuals with negative amyloid positron emission tomography (PET) scans, 281 with prodromal AD (mild cognitive impairment due to AD) and 285 with AD dementia who confirmed with positive amyloid PET scans participated in the study. We obtained high-resolution T1-weighted and diffusion tensor images and performed network analysis. We observed sex differences in the rich-club and feeder connections in patients with AD, suggesting lower structural connectivity strength in women than in men. We observed a significant group-by-sex interaction in the feeder connections, particularly in the thalamus. In addition, the connectivity strength of the thalamus in the feeder connections was significantly correlated with general cognitive function in only men with prodromal AD and women with AD dementia. Our findings provide important evidence for sex-specific alterations in the structural brain network related to AD.

Neurodegeneration or dysfunction in Phelan-McDermid syndrome? A multimodal approach with CSF and computational MRI

BackgroundPhelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood. Since symptoms of the autism spectrum, regression, and stagnation in development occur, we investigated whether neuroinflammatory and neurodegenerative processes may also play a role. To this end, we analysed biomarkers in cerebrospinal fluid (CSF) and parameters from magnetic resonance imaging with high-resolution structural T1w volumetry and diffusion tensor imaging analysis in 19 Phelan-McDermid syndrome patients.ResultsCSF showed no inflammation but abnormalities in tau protein and amyloid-ß concentrations, however, with no typical biomarker pattern as in Alzheimer’s disease. It could be demonstrated that these CSF changes were correlated with integrity losses of the fibres in the corticospinal tract as well as in the splenium and dorsal part of the cingulum. High CSF levels of tau protein were associated with loss of integrity of fibres in the corticospinal tract; lower levels of amyloid-ß were associated with decreasing integrity of fibre tracts of the splenium and posterior cingulate gyrus. Volumetric investigations showed global atrophy of the white matter, but not the grey matter, and particularly not in temporal or mesiotemporal regions, as is typical in later stages of Alzheimer’s disease.ConclusionsIn summary, alterations of neurodegenerative CSF markers in PMS individuals could be demonstrated which were correlated with structural connectivity losses of the corticospinal tract, the splenium, and the dorsal part of the cingulum, which can also be associated with typical clinical symptoms in these patients. These findings might represent a state of dysfunctional processes with ongoing degenerative and regenerative processes or a kind of accelerated aging. This study should foster further clinical diagnostics like tau- and amyloid-PET imaging as well as novel scientific approaches especially in basic research for further mechanistic proof.

Increased Cerebello-Prefrontal Connectivity Predicts Poor Executive Function in Congenital Heart Disease.

Children and adolescents with congenital heart disease (CHD) are at risk for cognitive impairments, such as executive function deficits and motor delays, which can impact their academic and adaptive functioning as well as their quality of life. We investigated whether alterations in connectivity between the prefrontal and cerebellar brain structures exist between CHD and control cohorts and if these alterations could predict cognitive or motor impairment among youths with CHD. 53 participants with CHD and 73 healthy control participants completed multi-modal magnetic resonance imaging (MRI) of the brain, including high-resolution diffusion tensor imaging at 3T. We measured connectivity from masked regions of interest in the cerebellum to the frontal cortex using a probabilistic tractography method. Participants also completed neuropsychological tests of cognitive and motor skills using the NIH Toolbox. In the CHD group, fractional anisotropy (FA) was increased in the cognitive loop connectivity pathways, including from the right cerebellum to the left thalamus (p = 0.0002) and from the left thalamus to the left medial frontal gyrus (MFG) (p = 0.0048) compared with the healthy control group. In contrast, there were no differences between CHD and controls in motor loop connectivity pathways. An increase in FA from the right thalamus to the MFG tract in the cognitive loop (posterior subdivision) predicted (p = 0.03) lower scores on the NIHTB tests, including those of executive functioning. A transient increase in connectivity of the cognitive loop in the adolescent group was observed relative to the child and adult groups. Our results suggest that selective alteration of cerebellum-cerebral connectivity circuitry within the cognitive loops predicts cognitive dysfunction in CHD youth. Our study suggests a critical period of cerebellar circuitry plasticity in the adolescent period in CHD subjects that drives neurocognitive function. Further replication and validation in other pediatric CHD cohorts is warranted for future work.

Construction of the MIITRA T1‐weighted and DTI templates of the older adult brain in a common space at 0.5mm resolution

AbstractBackgroundHigh resolution multimodal MRI templates of the older adult brain have the potential to facilitate template‐based studies of aging. As part of the Multichannel Illinois Institute of Technology &amp; Rush university Aging (MIITRA) atlas, the present work developed high quality 0.5mm isotropic resolution T1‐weighted (T1w) and diffusion tensor imaging (DTI) templates in common space using data from a large, diverse, community cohort of non‐demented older adults.Method Data T1w and DTI data were collected using two 3T MRI scanners on 400 non‐demented older adults (50% male;64.9‐98.9 yrs;54% white,43% black) (Bennett et al.,2018; Barnes et al.,2012). Template construction Step1: An unbiased initial T1w template was created by pairwise affine registration (Ridwan et al.,2021).Step2: Spatial normalization was driven by T1w and DTI data alternatively (Wu et al., 2019). All transformations were combined to minimize interpolations and applied to both modalities. A patch‐based tissue‐guided sparse‐representation approach was employed to compute the template (Ridwan et al.,2021).Step3: High spatial resolution templates were created based on principles of super‐resolution (Niaz et al.,2022)The resulting templates are referred to as MIITRA_0.5mm templates. Evaluation T1w and DTI data from 202 ADNI3 non‐demented older adults were used for evaluation.The MIITRA_0.5mm templates were compared to other high resolution templates and the templates including older adults in terms of image sharpness and spatial normalization accuracy of ADNI3 data when each template was used as a reference for normalization.ResultMIITRA_0.5mm templates exhibited higher image sharpness (Fig.1,2). MIITRA_0.5mm templates allowed the highest inter‐subject spatial normalization accuracy across spatially normalized ADNI3 data and required less deformation than other high‐resolution templates (Fig.3,4). It should be noted that 1mm templates require on average less deformation than high‐resolution templates because larger voxels limit local deformations. Finally, the MIITRA_0.5mm templates allowed higher inter‐modality spatial matching of normalized older adult data (Fig.5).ConclusionThis work developed high resolution T1w and DTI multimodal templates of the older adult brain for the MIITRA atlas. The new templates exhibited higher image quality, were more representative of the older adult brain, and allowed higher spatial normalization accuracy compared to other templates. The new templates will be available for download at www.nitrc.org/projects/miitra.

High-resolution diffusion tensor imaging and T2 mapping detect regional changes within the hippocampus in multiple sclerosis.

Hippocampus demyelinating lesions in multiple sclerosis (MS) have been frequently observed in ex vivo histopathological studies; however, they are difficult to image and quantify in vivo. Diffusion tensor imaging (DTI) and T2 mapping could potentially detect such regional in vivo changes if acquired with sufficient spatial resolution. The goal here was to evaluate whether there are focal hippocampal abnormalities in 43 MS patients (35 relapsing-remitting, eight secondary progressive) with and without cognitive impairment (CI) versus 43 controls using high-resolution 1 mm isotropic DTI, as well as complementary methods of T2-weighted and T2 mapping at 3 T. Abnormal hippocampus regions were identified voxel-by-voxel by using mean diffusivity (MD)/T2 thresholds and avoiding voxels attributed to cerebrospinal fluid. When compared with controls, averaged left/right whole hippocampus MD was higher in both MS groups, while lower fractional anisotropy (FA) and volume, and higher T2 relaxometry and T2-weighted signal values, were only significant in CI MS. The hippocampal MD and T2 images/maps were not uniformly affected and focal regions of elevated MD/T2 were evident in MS patients. Both CI and not CI MS groups showed greater proportional areas of the hippocampus with elevated MD, whereas only the CI group showed a greater proportional area of elevated T2 relaxation times or T2-weighted signal. Higher T2 relaxometry and T2-weighted signal values of elevated regions correlated with greater disability and whole hippocampus FA negatively correlated with physical fatigue. High-resolution hippocampus DTI and T2 mapping with less partial volume effects showed whole hippocampus abnormalities with regional elevations of MD/T2 in MS, which could be interpreted as potentially from demyelination, neuron loss, and/or inflammation, and which overall were more extensive in the hippocampus of patients with larger total brain lesion volumes and CI.

Fine Motor Skill Decline After Brain Radiation Therapy—A Multivariate Normal Tissue Complication Probability Study of a Prospective Trial

Brain radiation therapy can impair fine motor skills (FMS). Fine motor skills are essential for activities of daily living, enabling hand-eye coordination for manipulative movements. We developed normal tissue complication probability (NTCP) models for the decline in FMS after fractionated brain radiation therapy (RT). On a prospective trial, 44 patients with primary brain tumors received fractioned RT; underwent high-resolution volumetric magnetic resonance imaging, diffusion tensor imaging, and comprehensive FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS]; and Grooved Pegboard dominant/nondominant hands) at baseline and 6 months postRT. Regions of interest subserving motor function (including cortex, superficial white matter, thalamus, basal ganglia, cerebellum, and white matter tracts) were autosegmented using validated methods and manually verified. Dosimetric and clinical variables were included in multivariate NTCP models using automated bootstrapped logistic regression, least absolute shrinkage and selection operator logistic regression, and random forests with nested cross-validation. Half of the patients showed a decline on grooved pegboard test of nondominant hands, 17 of 42 (40.4%) on grooved pegboard test of -dominant hands, and 11 of 44 (25%) on DKEFS-MS. Automated bootstrapped logistic regression selected a 1-term model including maximum dose to dominant postcentral white matter. The least absolute shrinkage and selection operator logistic regression selected this term and steroid use. The top 5 variables in the random forest were all dosimetric: maximum dose to dominant thalamus, mean dose to dominant caudate, mean and maximum dose to the dominant corticospinal tract, and maximum dose to dominant postcentral white matter. This technique performed best with an area under the curve of 0.69 (95% CI, 0.68-0.70) on nested cross-validation. We present the first NTCP models for FMS impairment after brain RT. Dose to several supratentorial motor-associated regions of interest correlated with a decline in dominant-hand fine motor dexterity in patients with primary brain tumors in multivariate models, outperforming clinical variables. These data can guide prospective fine motor-sparing strategies for brain RT.

Parvalbumin as a neurochemical marker of the primate optic radiation

Parvalbumin (PV) is a calcium-binding protein that labels neuronal cell bodies in the magno and parvocellular layers of the primate lateral geniculate nucleus (LGN). Here we demonstrate that PV immunohistochemistry can also be used to trace the optic radiation (OR) of the marmoset monkey (Callithrix jacchus) from its LGN origin to its destinations in the primary visual cortex (V1), thus providing a high-resolution method for identification of the OR with single axon resolution. The emergence of fibers from LGN, their entire course and even the entry points to V1 were clearly defined in coronal, parasagittal, and horizontal sections of marmoset brain. In all cases, the trajectory revealed by PV staining paralleled that defined by high-resolution diffusion tensor imaging (DTI). We found that V1 was the exclusive target for the PV-containing fibers, with abrupt transitions in staining observed in the white matter at the border with area V2, and no evidence of PV-labeled axons feeding into other visual areas. Changes in the pattern of PV staining in the OR were detected following V1 lesions, demonstrating that this method can be used to assess the progress of retrograde degeneration of geniculocortical projections. These results suggest a technically simple approach to advance our understanding of a major white matter structure, which provides a cellular resolution suitable for the detection of microstructural variations during development, health and disease. Understanding the relationship between PV staining and DTI in non-human primates may also offer clues for improving the specificity and sensitivity of OR tractography for clinical purposes.

Column-based cortical depth analysis of the diffusion anisotropy and radiality in submillimeter whole-brain diffusion tensor imaging of the human cortical gray matter in vivo

High-resolution diffusion tensor imaging (DTI) can noninvasively probe the microstructure of cortical gray matter in vivo. In this study, 0.9-mm isotropic whole-brain DTI data were acquired in healthy subjects with an efficient multi-band multi-shot echo-planar imaging sequence. A column-based analysis that samples the fractional anisotropy (FA) and radiality index (RI) along radially oriented cortical columns was then performed to quantitatively analyze the FA and RI dependence on the cortical depth, cortical region, cortical curvature, and cortical thickness across the whole brain, which has not been simultaneously and systematically investigated in previous studies. The results showed characteristic FA and RI vs. cortical depth profiles, with an FA local maximum and minimum (or two inflection points) and a single RI maximum at intermediate cortical depths in most cortical regions, except for the postcentral gyrus where no FA peaks and a lower RI were observed. These results were consistent between repeated scans from the same subjects and across different subjects. They were also dependent on the cortical curvature and cortical thickness in that the characteristic FA and RI peaks were more pronounced i) at the banks than at the crown of gyri or at the fundus of sulci and ii) as the cortical thickness increases. This methodology can help characterize variations in microstructure along the cortical depth and across the whole brain in vivo, potentially providing quantitative biomarkers for neurological disorders.

Reorganization of brain networks in patients with temporal lobe epilepsy and comorbid headache

ObjectiveThe white matter structural network changes remain poorly understood in patients with temporal lobe epilepsy and comorbid headache (PWH). This study aimed at exploring topological changes in the structural network. MethodsTwenty-five PWH, 32 patients with temporal lobe epilepsy without headache, and 22 healthy controls were recruited in this study. High-resolution structural MRI and diffusion tensor imaging data were acquired from these participants. A graph theory-based approach was employed to characterize the topological properties of the structural network. A network-based statistical analysis was employed to explore abnormal connectivity alterations in PWH. ResultsCompared with healthy controls, PWH exhibited significantly decreased small-world index, shortest path length, increased clustering coefficient, global efficiency, and local efficiency. Patients with temporal lobe epilepsy and comorbid headache displayed a significantly reduced small-world index, shortest path length, and increased global efficiency when compared with patients with temporal lobe epilepsy without headache. In addition, PWH exhibited abnormal local network parameters, mainly located in the prefrontal, temporal, occipital, and parietal regions. Furthermore, network-based statistical analysis revealed that PWH had abnormal structural connections between the temporoparietal lobe, occipital lobe, insula, cingulate gyrus, and thalamus. ConclusionThis study reveals the abnormal white matter structural network alterations in PWH, allowing a better insight into the neuroanatomical mechanisms that predispose epileptic patients to comorbid headaches from the network levels.

Longitudinal hippocampal diffusion-weighted imaging and T2 relaxometry demonstrate regional abnormalities which are stable and predict subfield pathology intemporallobeepilepsy.

High-resolution (1 mm isotropic) diffusion tensor imaging (DTI) of the hippocampus in temporal lobe epilepsy (TLE) patients has shown patterns of hippocampal subfield diffusion abnormalities, which were consistent with hippocampal sclerosis (HS) subtype on surgical histology. The objectives of this longitudinal imaging study were to determine the stability of focal hippocampus diffusion changes over time in TLE patients, compare diffusion and quantitative T2 abnormalities of the sclerotic hippocampus, and correlate presurgical mean diffusivity (MD) and T2 maps with postsurgical histology. Nineteen TLE patients and 19 controls underwent two high-resolution (1 mm isotropic) DTI and 1.1 × 1.1 × 1 mm3 T2 relaxometry scans (in a subset of 16 TLE patients and 9 controls) of the hippocampus at 3T, with a 2.6 ± 0.8 year inter-scan interval. Within-participant hippocampal volume, MD and T2 were compared between the scans. Contralateral hippocampal changes 2.3 ± 1.0 years after surgery and ipsilateral preoperative MD maps versus postoperative subfield histopathology were evaluated in eight patients who underwent surgical resection of the hippocampus. Reduced volume and elevated MD and T2 of sclerotic hippocampi remained unchanged between longitudinal scans. Focal regions of elevated MD and T2 in bilateral hippocampi of HS TLE were detected consistently at both scans. Regions of high MD and T2 correlated and remained consistent over time. Volume, MD, and T2 remained unchanged in postoperative contralateral hippocampus. Regional elevations of MD identified subfield neuron loss on postsurgical histology with 88% sensitivity and 88% specificity. Focal T2 elevations identified subfield neuron loss with 75% sensitivity and 88% specificity. Diffusion and T2 abnormalities in ipsilateral and contralateral hippocampi remained unchanged between the scans suggesting permanent microstructural alterations. MD and T2 demonstrated good sensitivity and specificity to detect hippocampal subfield neuron loss on postsurgical histology, supporting the potential that high-resolution hippocampal DTI and T2 could be used to diagnose HS subtype before surgery.

Disturbed hippocampal intra-network in first-episode of drug-naïve major depressive disorder.

Complex networks inside the hippocampus could provide new insights into hippocampal abnormalities in various psychiatric disorders and dementia. However, evaluating intra-networks in the hippocampus using MRI is challenging. Here, we employed a high spatial resolution of conventional structural imaging and independent component analysis to investigate intra-networks structural covariance in the hippocampus. We extracted the intra-networks based on the intrinsic connectivity of each 0.9 mm isotropic voxel to every other voxel using a data-driven approach. With a total volume of 3 cc, the hippocampus contains 4115 voxels for a 0.9 mm isotropic voxel size or 375 voxels for a 2 mm isotropic voxel of high-resolution functional or diffusion tensor imaging. Therefore, the novel method presented in the current study could evaluate the hippocampal intra-networks in detail. Furthermore, we investigated the abnormality of the intra-networks in major depressive disorders. A total of 77 patients with first-episode drug-naïve major depressive disorder and 79 healthy subjects were recruited. The independent component analysis extracted seven intra-networks from hippocampal structural images, which were divided into four bilateral networks and three networks along the longitudinal axis. A significant difference was observed in the bilateral hippocampal tail network between patients with major depressive disorder and healthy subjects. In the logistic regression analysis, two bilateral networks were significant predictors of major depressive disorder, with an accuracy of 78.1%. In conclusion, we present a novel method for evaluating intra-networks in the hippocampus. One advantage of this method is that a detailed network can be estimated using conventional structural imaging. In addition, we found novel bilateral networks in the hippocampus that were disturbed in patients with major depressive disorders, and these bilateral networks could predict major depressive disorders.

Diffusion MRI alterations coincide with memory deficits in a novel hAβKI mouse model of Alzheimer’s Disease

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aβ Knock‐In (hAβKI) mouse. These mice exhibit age‐dependent cognitive and synaptic impairments. Preclinical neuroimaging was performed, specifically diffusion MRI (dMRI) to investigate brain‐wide structural alterations in conjunction with connectomic analyses across the hAβKI mouse lifespan.MethodhAβKI and WT mice were compared at 4, 12, and 18 months (mo) of age. Two cohorts were generated for: 1) behavior and long‐term potentiation (LTP), and 2) high resolution diffusion tensor imaging at 9.4T (30 directions b=3000 mm2/sec) to assess regional white and gray matter changes. Regional tissue features based on the AMBMC atlas were extracted from fractional anisotropy (FA), radial (RD), axial (AxD) and mean diffusivity (MD) parametric maps.ResultSignificant impairments in hippocampal LTP were observed in male hAβKI mice at 4mo of age relative to WT but not at 12 or 18mo. In contrast, in female hAβKI mice, LTP impairments were observed only at 12 and 18mo relative to WT. dMRI heatmaps of MD highlighted regional differences between sexes across time and genotype, with MD progressively decreasing with time. Male hAβKI mice had progressive changes within the brain with advancing age whereas the largest changes in females was at 12mo of age. AxD in 18mo male hAβKI mice was increased in 4 of 7 white matter regions but not in female hAβKI mice compared to WT.ConclusionIn summary, using the newly developed hAβKI mouse model of AD, we identified progressive altered regional dMRI tissue metrics. The hippocampal CA1 region appeared to be particularly vulnerable, findings consistent with observed impairments in LTP and behavior. MRI of new mouse models is a powerful tool to investigate tissue level modifications to brain structure and function to inform human disease.