Fractional Anisotropy Alterations Research Articles

Comprehensive Assessment of Ischemic Stroke in Nonhuman Primates: Neuroimaging, Behavioral, and Serum Proteomic Analysis.

Ischemic strokes, prevalence and impactful, underscore the necessity of advanced research models closely resembling human physiology. Our study utilizes nonhuman primates (NHPs) to provide a detailed exploration of ischemic stroke, integrating neuroimaging data, behavioral outcomes, and serum proteomics to elucidate the complex interplay of factors involved in stroke pathophysiology. We observed a consistent pattern in infarct volume, peaking at 1-month postmiddle cerebral artery occlusion (MCAO) and then stabilized. This pattern was strongly correlated to notable changes in motor function and working memory performance. Using diffusion tensor imaging (DTI), we detected significant alterations in fractional anisotropy (FA) and mean diffusivity (MD) values, signaling microstructural changes in the brain. These alterations closely correlated with the neurological and cognitive deficits that we observed, highlighting the sensitivity of DTI metrics in stroke assessment. Behaviorally, the monkeys exhibited a reliance on their unaffected limb for compensatory movements, a common response to stroke impairment. This adaptation, along with consistent DTI findings, suggests a significant impact of stroke on motor function and spatial perception. Proteomic analysis through MS/MS functional enrichment identified two distinct groups of proteins with significant changes post-MCAO. Notably, MMP9, THBS1, MB, PFN1, and YWHAZ were identified as potential biomarkers and therapeutic targets for ischemic stroke. Our results underscore the complex nature of stroke and advocate for an integrated approach, combining neuroimaging, behavioral studies, and proteomics, for advancing our understanding and treatment of this condition.

Amelioration of the brain structural connectivity is accompanied with changes of gut microbiota in a tuberous sclerosis complex mouse model

Tuberous sclerosis complex (TSC) is a genetic disease that causes benign tumors and dysfunctions in many organs, including the brain. Aside from the brain malformations, many individuals with TSC exhibit neuropsychiatric symptoms. Among these symptoms, autism spectrum disorder (ASD) is one of the most common co-morbidities, affecting up to 60% of the population. Past neuroimaging studies strongly suggested that the impairments in brain connectivity contribute to ASD, whether or not TSC-related. Specifically, the tract-based diffusion tensor imaging (DTI) analysis provides information on the fiber integrity and has been used to study the neuropathological changes in the white matter of TSC patients with ASD symptoms. In our previous study, curcumin, a diet-derived mTOR inhibitor has been shown to effectively mitigate learning and memory deficits and anxiety-like behavior in Tsc2+/− mice via inhibiting astroglial proliferation. Recently, gut microbiota, which is greatly influenced by the diet, has been considered to play an important role in regulating several components of the central nervous system, including glial functions. In this study, we showed that the abnormal social behavior in the Tsc2+/− mice can be ameliorated by the dietary curcumin treatment. Second, using tract-based DTI analysis, we found that the Tsc2+/− mice exhibited altered fractional anisotropy, axial and radial diffusivities of axonal bundles connecting the prefrontal cortex, nucleus accumbens, hypothalamus, and amygdala, indicating a decreased brain network. Third, the dietary curcumin treatment improved the DTI metrics, in accordance with changes in the gut microbiota composition. At the bacterial phylum level, we showed that the abundances of Actinobacteria, Verrucomicrobia, and Tenericutes were significantly correlated with the DTI metrics FA, AD, and RD, respectively. Finally, we revealed that the expression of myelin-associated proteins, myelin bassic protein (MBP) and proteolipid protein (PLP) was increased after the treatment. Overall, we showed a strong correlation between structural connectivity alterations and social behavioral deficits, as well as the diet-dependent changes in gut microbiota composition.

Baseline symptom-related white matter tracts predict individualized treatment response to 12-week antipsychotic monotherapies in first-episode schizophrenia

There is significant heterogeneity in individual responses to antipsychotic drugs, but there is no reliable predictor of antipsychotics response in first-episode psychosis. This study aimed to investigate whether psychotic symptom-related alterations in fractional anisotropy (FA) and mean diffusivity (MD) of white matter (WM) at the early stage of the disorder may aid in the individualized prediction of drug response. Sixty-eight first-episode patients underwent baseline structural MRI scans and were subsequently randomized to receive a single atypical antipsychotic throughout the first 12 weeks. Clinical symptoms were evaluated using the eight “core symptoms” selected from the Positive and Negative Syndrome Scale (PANSS-8). Follow-up assessments were conducted at the 4th, 8th, and 12th weeks by trained psychiatrists. LASSO regression model and cross-validation were conducted to examine the performance of baseline symptom-related alterations FA and MD of WM in the prediction of individualized treatment outcome. Fifty patients completed both clinical follow-up assessments by the 8th and 12th weeks. 30 patients were classified as responders, and 20 patients were classified as nonresponders. At baseline, the altered diffusion properties of fiber tracts in the anterior thalamic radiation, corticospinal tract, callosum forceps minor, longitudinal fasciculi (ILF), inferior frontal-occipital fasciculi (IFOF) and superior longitudinal fasciculus (SLF) were related to the severity of symptoms. These abnormal fiber tracts, especially the ILF, IFOF, and SLF, significantly predicted the response to antipsychotic treatment at the individual level (AUC = 0.828, P < 0.001). These findings demonstrate that early microstructural WM changes contribute to the pathophysiology of psychosis and may serve as meaningful individualized predictors of response to antipsychotics.

Brain white matter microstructural changes in chemotherapy-treated older long-term breast cancer survivors.

To assess white matter microstructural changes in older long-term breast cancer survivors 5-15 years post-chemotherapy treatment. Breast cancer survivors aged 65 years or older who underwent chemotherapy (C+) and who did not undergo chemotherapy (C-) and age- and sex-matched healthy controls (HC) were enrolled at time point 1 (TP1) and followed for 2 years for time point 2 (TP2). All participants underwent brain MRI with diffusion tensor images and neuropsychological (NP) testing with the NIH Toolbox Cognition Battery. Tract-based spatial statistics (TBSS) analysis was performed on the diffusion tensor images to assess white matter microstructural changes with the fractional anisotropy (FA) parameter. There were significant longitudinal alterations in FA within the C+ group over time. The C+ group showed diminished FA in the body and genu of corpus callosum, anterior corona radiate, and external capsule on both the whole brain and region of interest (ROI) based analyses after p < 0.05 family-wise error (FWE) correction. However, there were no significant group differences between the groups at TP1. Additionally, at TP1, a positive correlation (R = 0.58, p = 0.04) was observed between the FA value of the anterior corona radiata and the crystallized composite score in the C+ group. Brain white matter microstructural alterations may be the underlying neural correlates of cognitive changes in older breast cancer survivors who had chemotherapy treatment years ago.

Hippocampus‐associated tract degradation follows differential DTI patterns and is influenced by amyloid in MCI patients

AbstractBackgroundDiffusion tensor imaging (DTI) has been leveraged to understand microstructural alterations to limbic and cortico‐cortical tracts in Alzheimer’s disease (AD). However, investigation into the key changes and patterns of fractional anisotropy (FA) and mean diffusivity (MD) metrics in the early stages of MCI has not been widely investigated. This study aimed to establish whether the early DTI white matter tract changes in MCI patients are decoupled and whether amyloid positivity (Aβ+/Aβ‐) is associated with early tract degradation.Method171 participants (103 MCI &amp; 73 CN) were recruited from the AD Neuroimaging Initiative (ADNI; adni.loni.usc.edu) database. For each participant, FA and MD maps were obtained at their baseline scan and voxel wise analysis was carried out using FSL (https://fsl.fmrib.ox.ac.uk/fsl/) and Tract‐Based Spatial Statistics (https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/TBSS). Students t‐tests were conducted on the FA and MD changes in hippocampal WM tracts, previously identified as areas of potential early degradation. Comparisons between CN and MCI groups were made along Aβ+ and Aβ‐ groups.ResultWe found evidence for WM degradation, indicated by lower FA scores in MCI participants compared with controls, in the specific regions of interest of the fornix (p = 0.004) and tapetum (p = 0.012). Mean diffusivity was increased in the MCI group compared to CN in areas of the fornix (p &lt; 0.001), consistent with FA alterations, yet differed from areas identified in FA changes owing to changes in the uncinate fasciculus (p = 0.022) and cingulum (p = 0.003). Comparison of DTI metrics in the fornix between amyloid status groups revealed that Aβ+ participants had significantly lower FA compared to Aβ‐ participants (p = 0.047), but MD did not significantly differ.ConclusionThese results confirm the notion that WM tract integrity degradation in the tract apparatus surrounding the hippocampus occur early in the AD trajectory. However, results indicate that FA alterations occur in different patterns to that of MD and that amyloid may influence these patterns. This supports the idea that efforts to develop therapeutics which maintain WM tract integrity early may be key to slowing AD progression.

Diffusion tensor imaging identifies atrial regional changes associated with atrial fibrillation remodelling

Abstract Background Structural remodeling in the context of persistent atrial fibrillation (PAF) has been mainly characterized by imaging techniques focused on fibrosis detection. Diffusion tensor imaging (DTI) has demonstrated its direct relationship with histological properties and myocyte organization, which may provide a more complete structural information. However, the potential of DTI in the characterization of the AF-related structural substrate remains unknown. Purposes To evaluate the performance of DTI-derived parameters to characterise the structural remodelling derived from persistent AF and its relationship with specific atrial regions associated with AF maintenance (i.e., driver regions). Methods Two experimental groups of pigs were studied: control (n=7) and PAF (n=10). The PAF swine model was developed using rapid atrial pacing until the animals reached a stage of self-sustained PAF. The AV node was ablated to prevent heart failure due to fast ventricular activation rates. A second lead in the right ventricular was used for ventricular pacing at 60-110 bpm. Animals with PAF were studied after ≥ 6 months in self-sustained persistent AF. AF animals underwent invasive electroanatomical to identify driver regions based on instantaneous frequency modulation maps. After euthanasia, explanted hearts from AF animals and controls underwent DTI including 15 diffusion weighted images with a b-value of 600 s/mm² plus a non-DWI volume (isotropic resolution, 0.6 mm³). DTI images were segmented and divided into 13 atrial anatomical regions. Driver regions in AF animals were also segmented and classified as functional regions of interest (ROIs) (Figure 2B). Afterwards, diffusion tensors were estimated and scalar features were analyzed (Figures 1A and 2A) according to both anatomical and functional ROIs. Results DTI analysis in AF animals revealed region-specific structural remodelling (Figure 1B). Compared to controls, PAF animals showed an increased fractional anisotropy (FA) in both right and left atrial free walls (Figure 1C). Other anatomical regions, such as the superior vena cava (SVC), the coronary sinus (CS) or the left atrium roof developed higher axial diffusivities in AF compared to controls (Figure 1D), without significant alterations in FA (Figure 1C). AF driver regions were frequently located in the CS, the SVC and the LAA (Figure 2C). AF driver ROIs into the CS and the SVC showed intracase increased diffusivities and decreased linear indexes compared to non-driver regions. However, AF driver ROIs in the LAA showed increased intervoxel main eigenvector dispersion in contrast to non-driver ROIs (Figure 2C). Conclusion DTI sequences provide atrial structural information associated with functional tissue properties relevant for AF maintenance.

White matter alterations in mild cognitive impairment revealed by meta-analysis of diffusion tensor imaging using tract-based spatial statistics.

The neuropathological mechanism of mild cognitive impairment (MCI) remains unclarified. Diffusion tensor imaging (DTI) studies revealed white matter (WM) microarchitecture alterations in MCI, but consistent findings and conclusions have not yet been drawn. The present coordinate-based meta-analysis (CBMA) of tract-based spatial statistics (TBSS) studies aimed to identify the most prominent and robust WM abnormalities in patients with MCI. A systematic search of relevant studies was conducted through January 2022 to identify TBSS studies comparing fractional anisotropy (FA) between MCI patients and healthy controls (HC). We used the seed-based d mapping (SDM) software to achieve the CBMA and analyze regional FA alterations in MCI. Meta-regression analysis was subsequently applied to explore the potential associations between clinical variables and FA changes. MCI patients demonstrated significantly decreased FA in widely distributed areas in the corpus callosum (CC), including the genu, body, and splenium of the CC, as well as one cluster in the left striatum. FA in the body of the CC and in three clusters in the splenium of the CC was negatively associated with the mean age. Additionally, FA in the genu of the CC and in three clusters in the splenium of the CC had negative correlations with the MMSE scores. Disrupted integrities of the CC and left striatum might play vital roles in the process of cognitive decline. These findings enhanced our understanding of the neural mechanism underlying WM neurodegeneration in MCI and provided perspectives for the early detection and intervention of dementia.Registration number: CRD42022235716.

Characterization of FTLD spectrum through advanced diffusion-weighted MRI metrics: a connectome approach (P11-6.003)

<h3>Objective:</h3> To investigate structural alterations in brain network of patients within the frontotemporal lobar degeneration (FTLD) spectrum using connectome analysis with advanced diffusion-weighted MRI metrics. <h3>Background:</h3> MRI connectomics is a promising tool to describe network-based degeneration in neurodegenerative diseases. Neurite orientation dispersion and density imaging (NODDI) has shown to provide novel insights on structural connectivity alterations. <h3>Design/Methods:</h3> Thirty-four behavioral-variant frontotemporal dementia (bvFTD), 11 semantic variant primary progressive aphasia (svPPA), 11 nonfluent (nfvPPA) patients and 48 healthy controls underwent multi-shell diffusion MRI. Fractional anisotropy (FA) maps were computed. Intra-cellular Volume Fraction (ICVF) maps were also estimated using NODDI, providing a direct quantification of neurite integrity. Graph analysis and connectomics assessed global and local structural topological network properties and regional structural connectivity. <h3>Results:</h3> Overall, widespread structural changes were observed in bvFTD patients relative to healthy controls and svPPA patients in terms of FA-derived network properties. nfvPPA patients also showed altered FA topological properties at global level compared to healthy controls. Sum of node weights (SN) in the sensorimotor lobe revealed that nfvPPA patients showed an altered connection strength compared to svPPA. Moreover, nfvPPA patients showed a significant decreased FA in the left hemispheric fronto-temporal-insular regions relative to controls. Considering ICVF, more severe alterations compared to FA maps allowed to find differences also between svPPA and nfvPPA patients. ICVF graph analysis measures also showed that svPPA had a lower degree centrality and SN in the temporal lobe compared to controls. <h3>Conclusions:</h3> These findings suggest that conventional diffusion-tensor measures might be sensitive enough to highlight vulnerable connections in the FTLD spectrum. However, ICVF demonstrated to be a more specific biomarker to differentiate FTLD syndromes. Specifically, the benefits emerged in the differentiation between svPPA patients and other groups. <b>Disclosure:</b> Federica Agosta has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Philips. Federica Agosta has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier INC. Silvia Basaia has nothing to disclose. Dr. Facente has nothing to disclose. Ms. Cividini has nothing to disclose. Dr. Spinelli has nothing to disclose. The institution of Elisa Canu has received research support from Italian Ministry of Health . Dr. Castelnovo has nothing to disclose. Giuseppe Magnani has nothing to disclose. Dr. Caso has nothing to disclose. Paola Caroppo has nothing to disclose. Sara Prioni has nothing to disclose. Miss Villa has nothing to disclose. Lucio Tremolizzo has nothing to disclose. Dr. Appollonio has nothing to disclose. Dr. Silani has nothing to disclose. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bayer, Biogen Idec, Merck-Serono, Novartis, Roche, Sanofi Genzyme, Takeda, and Teva Pharmaceutical Industries. Dr. Filippi has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Dr. Filippi has received research support from Biogen Idec, Merck-Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

White matter tract abnormalities are associated with executive dysfunction in temporal lobe epilepsy and hippocampal sclerosis (P12-1.010)

<h3>Objective:</h3> To evaluate the role of white-matter tract involvement in executive dysfunction in patients with temporal lobe epilepsy and unilateral hippocampal sclerosis (TLE-HS). <h3>Background:</h3> TLE-HS patients frequently display executive dysfunction (ED). The neuroanatomical substrate of ED in TLE-HS remains poorly understood. In this study, we investigated the role of white-matter tract involvement in ED in TLE-HS. <h3>Design/Methods:</h3> Patients with unilateral TLE-HS, aged 17–55, education&gt;=8 years, IQ&gt;=70, EEG findings of unilateral or bilateral temporal discharges were studied. Patients and healthy controls fulfilling the same inclusion criteria underwent the Stroop Color and Word Test (SCWT) and a 3T MRI with DTI sequences. DTI Fractional Anisotropy (FA) data was extracted and analyzed using FSL. FA maps were compared with Tract-Based Spatial Statistics (TBSS) voxel-wise analysis. Patients were classified as ED if performance in the SCWT was below minus 1.5 (−1.5) Standard Deviations of the mean performance of healthy controls. <h3>Results:</h3> 49 patients (30 left and 19 right HS) underwent the SCWT. Performance did not differ between right and left HS. Patients with normal and impaired executive function did not differ in disease duration, antiseizure medication load, and seizure frequency. Both patient groups showed diffuse FA decrease when compared to healthy controls. Compared to TLE-HS patients with normal SCWT performance, patients with ED had more pronounced FA alterations, showing statistically significant decreased FA in the superior longitudinal fasciculi, body of the corpus callosum, forceps major, corona radiata, inferior frontal-occipital fasciculus, uncinate fasciculus and corticospinal tract, and right thalamic radiations. <h3>Conclusions:</h3> In this TLE-HS patient population, executive dysfunction was associated with more pronounced widespread WM tract damage, in comparison with TLE-HS patients with preserved executive function. This finding underscores the role of microstructural WM damage in executive dysfunction in TLE-HS. <b>Disclosure:</b> Miss Solti has nothing to disclose. Mr. Mahler Ferreira Oliveira has nothing to disclose. Carla Adda has nothing to disclose. Rosa Valerio has nothing to disclose. Dr. Jorge has nothing to disclose. Katarina Lyra has nothing to disclose. Mr. Pastorello has nothing to disclose. Claudia Leite has nothing to disclose. Maria Otaduy has nothing to disclose. Dr. Castro has nothing to disclose.

White matter microstructure and executive functions in congenital heart disease from childhood to adulthood: A pooled case–control study

ABSTRACT Congenital heart disease (CHD) patients are at risk for alterations in the cerebral white matter microstructure (WMM) throughout development. It is unclear whether the extent of WMM alterations changes with age, especially during adolescence when the WMM undergoes rapid maturation. We investigated differences in WMM between patients with CHD and healthy controls from childhood until early adulthood in a pooled sample of children, adolescents, and young adults. The association between WMM and EF was assessed. Patients with CHD (N=78) and controls (N=137) between 9 and 32 years of age underwent diffusion tensor imaging and an executive function test-battery. Mean fractional anisotropy (FA) was calculated for each white matter tract. Linear regression tested age and group effects (CHD vs control) and their interaction on FA. Relative Variable Importance (RI) estimated the independent contribution of tract FA, presence of CHD, CHD complexity, and parental education to the variability in EF. Mean FA was lower in patients compared to controls in almost all tracts (p between 0.057 and <0.001). WMM alterations in patients were not different depending on age (all interaction effects p>0.074). Predictors of EF were CHD group (RI=43%), parental education (RI=23%), CHD complexity (RI=10%), FA of the hippocampal cingulum (RI=6%) and FA of the corticospinal tract (RI=6%). The lack of group-FA-interactions indicates that the extent of altered FA remains similar across age. Altered FA is associated with EF impairments. CHD is a chronic disease with cerebral and neurocognitive impairments persisting into adulthood and, thus, long-term follow-up programs may improve overall outcome for this population.

Alterations of brain microstructures in a mouse model of prenatal opioid exposure detected by diffusion MRI

Growing opioid use among pregnant women is fueling a crisis of infants born with prenatal opioid exposure. A large body of research has been devoted to studying the management of opioid withdrawal during the neonatal period in these infants, but less substantive work has explored the long-term impact of prenatal opioid exposure on neurodevelopment. Using a translationally relevant mouse model of prenatal methadone exposure (PME), the aim of the study is to investigate the cerebral microstructural differences between the mice with PME and prenatal saline exposure (PSE). The brains of eight-week-old male offspring with either PME (n = 15) or PSE (n = 15) were imaged using high resolution in-vivo diffusion magnetic resonance imaging on a 9.4 Tesla small animal scanner. Brain microstructure was characterized using diffusion tensor imaging (DTI) and Bingham neurite orientation dispersion and density imaging (Bingham-NODDI). Voxel-based analysis (VBA) was performed using the calculated microstructural parametric maps. The VBA showed significant (p < 0.05) bilateral alterations in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), orientation dispersion index (ODI) and dispersion anisotropy index (DAI) across several cortical and subcortical regions, compared to PSE. Particularly, in PME offspring, FA, MD and AD were significantly higher in the hippocampus, dorsal amygdala, thalamus, septal nuclei, dorsal striatum and nucleus accumbens. These DTI-based results suggest widespread bilateral microstructural alterations across cortical and subcortical regions in PME offspring. Consistent with the observations in DTI, Bingham-NODDI derived ODI exhibited significant reduction in PME offspring within the hippocampus, dorsal striatum and cortex. NODDI-based results further suggest reduction in dendritic arborization in PME offspring across multiple cortical and subcortical regions. To our best knowledge, this is the first study of prenatal opioid exposure to examine microstructural organization in vivo. Our findings demonstrate perturbed microstructural complexity in cortical and subcortical regions persisting into early adulthood which could interfere with critical neurodevelopmental processes in individuals with prenatal opioid exposure.

Structural white matter characteristics for working memory and switching/inhibition in children with reading difficulties: The role of the left superior longitudinal fasciculus.

Reading difficulties (RDs) are characterized by slow and inaccurate reading as well as additional challenges in cognitive control (i.e., executive functions, especially in working memory, inhibition, and visual attention). Despite evidence demonstrating differences in these readers' language and visual processing abilities, white matter differences associated with executive functions (EFs) difficulties in children with RDs are scarce. Structural correlates for reading and EFs in 8- to 12-year-old children with RDs versus typical readers (TRs) were examined using diffusion tensor imaging (DTI) data. Results suggest that children with RDs showed significantly lower reading and EF abilities versus TRs. Lower fractional anisotropy (FA) in left temporo-parietal tracts was found in children with RDs, who also showed positive correlations between reading and working memory and switching/inhibition scores and FA in the left superior longitudinal fasciculus (SLF). FA in the left SLF predicted working memory performance mediated by reading ability in children with RDs but not TRs. Our findings support alterations in white matter tracts related to working memory, switching/inhibition, and overall EF challenges in children with RDs and the linkage between working memory difficulties and FA alterations in the left SLF in children with RDs via reading.

Applying dimensional psychopathology: transdiagnostic prediction of executive cognition using brain connectivity and inflammatory biomarkers.

The association between executive dysfunction, brain dysconnectivity, and inflammation is a prominent feature across major psychiatric disorders (MPDs), schizophrenia, bipolar disorder, and major depressive disorder. A dimensional approach is warranted to delineate their mechanistic interplay across MPDs. This single site study included a total of 1543 participants (1058 patients and 485 controls). In total, 1169 participants underwent diffusion tensor and resting-state functional magnetic resonance imaging (745 patients and 379 controls completed the Wisconsin Card Sorting Test). Fractional anisotropy (FA) and regional homogeneity (ReHo) assessed structural and functional connectivity, respectively. Pro-inflammatory cytokine levels [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α] were obtained in 325 participants using blood samples collected with 24 h of scanning. Group differences were determined for main measures, and correlation and mediation analyses and machine learning prediction modeling were performed. Executive deficits were associated with decreased FA, increased ReHo, and elevated IL-1β and IL-6 levels across MPDs, compared to controls. FA and ReHo alterations in fronto-limbic-striatal regions contributed to executive deficits. IL-1β mediated the association between FA and cognition, and IL-6 mediated the relationship between ReHo and cognition. Executive cognition was better predicted by both brain connectivity and cytokine measures than either one alone for FA-IL-1β and ReHo-IL-6. Transdiagnostic associations among brain connectivity, inflammation, and executive cognition exist across MPDs, implicating common neurobiological substrates and mechanisms for executive deficits in MPDs. Further, inflammation-related brain dysconnectivity within fronto-limbic-striatal regions may represent a transdiagnostic dimension underlying executive dysfunction that could be leveraged to advance treatment.

Repetitive Transcranial Magnetic Stimulation Induces Quantified Functional and Structural Changes in Subcortical Stroke: A Combined Arterial Spin Labeling Perfusion and Diffusion Tensor Imaging Study.

PurposeTo explore the changes of cerebral blood flow (CBF) and fractional anisotropy (FA) in stroke patients with motor dysfunction after repetitive transcranial magnetic stimulation (rTMS) treatment, and to better understand the role of rTMS on motor rehabilitation of subcortical stroke patients from the perfusion and structural level.Materials and MethodsIn total, 23 first-episode acute ischemic stroke patients and sixteen healthy controls (HCs) were included. The patients were divided into the rTMS and sham group. The rehabilitation assessments and examination of perfusion and structural MRI were performed before and after rTMS therapy for each patient. Voxel-based analysis was used to detect the difference in CBF and FA among all three groups. The Pearson correlation analysis was conducted to evaluate the relationship between the CBF/FA value and the motor scales.ResultsAfter rTMS, significantly increased CBF was found in the ipsilesional supplementary motor area, postcentral gyrus, precentral gyrus, pons, medulla oblongata, contralesional midbrain, superior cerebellar peduncle, and middle cerebellar peduncle compared to that during the prestimulation and in the sham group, these fasciculi comprise the cortex-pontine-cerebellum-cortex (CPC) loop. Besides, altered CBF in the ipsilesional precentral gyrus, postcentral gyrus, and pons was positively associated with the improved Fugl-Meyer assessment (FMA) scores. Significantly decreased FA was found in the contralesional precentral gyrus, increased FA was found in the ipsilesional postcentral gyrus, precentral gyrus, contralesional supplementary motor area, and bilateral cerebellum, these fasciculi comprise the corticospinal tract (CST). The change of FMA score was positively correlated with altered FA value in the ipsilesional postcentral gyrus and negatively correlated with altered FA value in the contralesional precentral gyrus.ConclusionOur results suggested that rTMS could facilitate the motor recovery of stroke patients. High frequency could promote the improvement of functional activity of ipsilesional CPC loop and the recovery of the microstructure of CST.

The impact of levamisole and alcohol on white matter microstructure in adult chronic cocaine users.

Previous brain imaging studies with chronic cocaine users (CU) using diffusion tensor imaging (DTI) mostly focused on fractional anisotropy to investigate white matter (WM) integrity. However, a quantitative interpretation of fractional anisotropy (FA) alterations is often impeded by the inherent limitations of the underlying tensor model. A more fine‐grained measure of WM alterations could be achieved by measuring fibre density (FD). This study investigates this novel DTI metric comparing 23 chronic CU and 32 healthy subjects. Quantitative hair analysis was used to determine intensity of cocaine and levamisole exposure—a cocaine adulterant with putative WM neurotoxicity. We first assessed the impact of cocaine use, levamisole exposure and alcohol use on group differences in WM integrity. Compared with healthy controls, all models revealed cortical reductions of FA and FD in CU. At the within‐patient group level, we found that alcohol use and levamisole exposure exhibited regionally different FA and FD alterations than cocaine use. We found mostly negative correlations of tract‐based WM associated with levamisole and weekly alcohol use. Specifically, levamisole exposure was linked with stronger WM reductions in the corpus callosum than alcohol use. Cocaine use duration correlated negatively with FA and FD in some regions. Yet, most of these correlations did not survive a correction for multiple testing. Our results suggest that chronic cocaine use, levamisole exposure and alcohol use were all linked to significant WM impairments in CU. We conclude that FD could be a sensitive marker to detect the impact of the use of multiple substances on WM integrity in cocaine but also other substance use disorders.

Longitudinal whole-brain analysis of multi-subject diffusion data in diffuse axonal injury.

Diffuse axonal injury occurs with high acceleration and deceleration forces in traumatic brain injury (TBI). This lesion leads to disarrangement of the neuronal network, which can result in some degree of deficiency. The Extended Glasgow Outcome Scale (GOS-E) is the primary outcome instrument for the evaluation of TBI victims. Diffusion tensor imaging (DTI) assesses white matter (WM) microstructure based on the displacement distribution of water molecules. To investigate WM microstructure within the first year after TBI using DTI, the patient's clinical outcomes, and associations. We scanned 20 moderate and severe TBI victims at 2 months and 1 year after the event. Imaging processing was done with the FMRIB software library; we used the tract-based spatial statistics software yielding fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) for statistical analyses. We computed the average difference between the two measures across subjects and performed a one-sample t-test and threshold-free cluster enhancement, using a corrected p-value < 0.05. Clinical outcomes were evaluated with the GOS-E. We tested for associations between outcome measures and significant mean FA clusters. Significant clusters of altered FA were identified anatomically using the JHU WM atlas. We found increasing spotted areas of FA with time in the right brain hemisphere and left cerebellum. Extensive regions of increased MD, RD, and AD were observed. Patients presented an excellent overall recovery. There were no associations between FA and outcome scores, but we cannot exclude the existence of a small to moderate association.

Quantification of changes in white matter tract fibers in idiopathic normal pressure hydrocephalus based on diffusion spectrum imaging

PurposePatients with idiopathic normal pressure hydrocephalus (iNPH) present white-matter abnormalities. The analytical methods described to date only measure mean diffusion parameter alterations of iNPH-specific brain regions or in a certain fasciculus. This study quantitatively analyzed whether iNPH-tract abnormalities are confined to specific sections or involve entire fibers based on diffusion spectrum imaging (DSI). MethodTwenty-two patients with iNPH and 20 normally aging subjects were included. The 18 main tracts in the brain of each subject were extracted, and the diffusion parameters of 100 equidistant nodes on each fiber were calculated to quantitatively evaluate integrity changes in different regions along these tracts. Two diffusion metrics were measured, i.e., general fractional anisotropy (GFA) and fractional anisotropy (FA). ResultsCompared to normally aging (P < 0.05), in iNPH, the GFA and FA of the left uncinate fasciculus and FA of the bilateral superior longitudinal fasciculus 1 were reduced in areas where the entire fiber was involved (%nodes with significant differences > 90%). Most other fasciculi detected presented GFA or FA alterations limited to specific regions. Increased and decreased GFA or FA co-occurred in different sections of the same fibers, including the corticospinal tract and left thalamic radiation posterior in iNPH. ConclusionsFew iNPH fibers presented diffusion abnormalities involving nearly all tracts. Most fiber abnormalities in iNPH were confined to specific areas, and different parts of the same fasciculus showed diverse diffusion alterations in few cases. This DSI-based tract analysis provided detailed information on iNPH white-matter changes.

White matter microstructure and the clinical risk for psychosis: A diffusion tensor imaging study of individuals with basic symptoms and at ultra-high risk

BackgroundWidespread white matter abnormalities are a frequent finding in chronic schizophrenia patients. More inconsistent results have been provided by the sparser literature on at-risk states for psychosis, i.e., emerging subclinical symptoms. However, considering risk as a homogenous construct, an approach of earlier studies, may impede our understanding of neuro-progression into psychosis. MethodsAn analysis was conducted of 3-Tesla MRI diffusion and symptom data from 112 individuals (mean age, 21.97 ± 4.19) within two at-risk paradigm subtypes, only basic symptoms (n = 43) and ultra-high risk (n = 37), and controls (n = 32). Between-group comparisons (involving three study groups and further split based on the subsequent transition to schizophrenia) of four diffusion-tensor-imaging-derived scalars were performed using voxelwise tract-based spatial statistics, followed by correlational analyses with Structured Interview for Prodromal Syndromes responses. ResultsRelative to controls, fractional anisotropy was lower in the splenium of the corpus callosum of ultra-high-risk individuals, but only before stringent multiple-testing correction, and negatively correlated with General Symptom severity among at-risk individuals. At-risk participants who transitioned to schizophrenia within 3 years, compared to those that did not transition, had more severe WM differences in fractional anisotropy and radial diffusivity (particularly in the corpus callosum, anterior corona radiata, and motor/sensory tracts), which were even more extensive compared to healthy controls. ConclusionsThese findings align with the subclinical symptom presentation and more extensive disruptions in converters, suggestive of severity-related demyelination or axonal pathology. Fine-grained but detectable differences among ultra-high-risk subjects (i.e., with brief limited intermittent and/or attenuated psychotic symptoms) point to the splenium as a discrete site of emerging psychopathology, while basic symptoms alone were not associated with altered fractional anisotropy.

DNA Methylation Basis in the Effect of White Matter Integrity Deficits on Cognitive Impairments and Psychopathological Symptoms in Drug-Naive First-Episode Schizophrenia.

Background: Mounting evidence from diffusion tensor imaging (DTI) and epigenetic studies, respectively, confirmed the abnormal alterations of brain white matter integrity and DNA methylation (DNAm) in schizophrenia. However, few studies have been carried out in the same sample to simultaneously explore the WM pathology relating to clinical behaviors, as well as the DNA methylation basis underlying the WM deficits.Methods: We performed DTI scans in 42 treatment-naïve first-episode schizophrenia patients and 38 healthy controls. Voxel-based method of fractional anisotropy (FA) derived from DTI was used to assess WM integrity. Participants' peripheral blood genomic DNAm status, quantified by using Infinium® Human Methylation 450K BeadChip, was examined in parallel with DTI scanning. Participants completed Digit Span test and Trail Making test, as well as Positive and Negative Syndrome Scale measurement. We acquired genes that are differentially expressed in the brain regions with abnormal FA values according to the Allen anatomically comprehensive atlas, obtained DNAm levels of the corresponding genes, and then performed Z-test to compare the differential epigenetic-imaging associations (DEIAs) between the two groups.Results: Significant decreases of FA values in the patient group were in the right middle temporal lobe WM, right cuneus WM, right anterior cingulate WM, and right inferior parietal lobe WM, while the significant increases were in the bilateral middle cingulate WM (Ps < 0.01, GRF correction). Abnormal FA values were correlated with patients' clinical symptoms and cognitive impairments. In the DEIAs, patients showed abnormal couple patterns between altered FA and DNAm components, for which the enriched biological processes and pathways could be largely grouped into three biological procedures: the neurocognition, immune, and nervous system.Conclusion: Schizophrenia may not cause widespread neuropathological changes, but subtle alterations affecting local cingulum WM, which may play a critical role in positive symptoms and cognitive impairments. This imaging-epigenetics study revealed for the first time that DNAm of genes enriched in neuronal, immunologic, and cognitive processes may serve as the basis in the effect of WM deficits on clinical behaviors in schizophrenia.

Associations between attention-deficit hyperactivity disorder (ADHD) symptom remission and white matter microstructure: A longitudinal analysis.

Background:Attention-deficit hyperactivity disorder (ADHD) is associated with white matter (WM) microstructure. Our objective was to investigate how WM microstructure is longitudinally related to symptom remission in adolescents and young adults with ADHD.Methods:We obtained diffusion-weighted imaging (DWI) data from 99 participants at two timepoints (mean age baseline: 16.91 years, mean age follow-up: 20.57 years). We used voxel-wise Tract-Based Spatial Statistics (TBSS) with permutation-based inference to investigate associations of inattention (IA) and hyperactivity-impulsivity (HI) symptom change with fractional anisotropy (FA) at baseline, follow-up, and change between time-points.Results:Remission of combined HI and IA symptoms was significantly associated with reduced FA at follow-up in the left superior longitudinal fasciculus and the left corticospinal tract (CST; PFWE = 0.038 and PFWE = 0.044, respectively), mainly driven by an association between HI remission and follow-up CST FA (PFWE = 0.049). There was no significant association of combined symptom decrease with FA at baseline or with changes in FA between the two assessments.Conclusions:In this longitudinal DWI study of ADHD using dimensional symptom scores, we show that greater symptom decrease is associated with lower follow-up FA in specific WM tracts. Altered FA thus may appear to follow, rather than precede, changes in symptom remission. Our findings indicate divergent WM developmental trajectories between individuals with persistent and remittent ADHD, and support the role of prefrontal and sensorimotor tracts in the remission of ADHD.