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Background The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. The objective of this study was to develop Tan IIA-loaded nanoparticles (Tan IIA-NPs) and to evaluate their therapeutic effects on cerebral pathological changes and consequent motor function deficits in a pig ischemic stroke model. Results Tan IIA-NP treated neural stem cells showed a reduction in SOD activity in in vitro assays demonstrating antioxidative effects. Ischemic stroke pigs treated with Tan IIA-NPs showed reduced hemispheric swelling when compared to vehicle only treated pigs (7.85 ± 1.41 vs. 16.83 ± 0.62%), consequent midline shift (MLS) (1.72 ± 0.07 vs. 2.91 ± 0.36 mm), and ischemic lesion volumes (9.54 ± 5.06 vs. 12.01 ± 0.17 cm3) when compared to vehicle-only treated pigs. Treatment also lead to lower reductions in diffusivity (−37.30 ± 3.67 vs. −46.33 ± 0.73%) and white matter integrity (−19.66 ± 5.58 vs. −30.11 ± 1.19%) as well as reduced hemorrhage (0.85 ± 0.15 vs 2.91 ± 0.84 cm3) 24 h post-ischemic stroke. In addition, Tan IIA-NPs led to a reduced percentage of circulating band neutrophils at 12 (7.75 ± 1.93 vs. 14.00 ± 1.73%) and 24 (4.25 ± 0.48 vs 5.75 ± 0.85%) hours post-stroke suggesting a mitigated inflammatory response. Moreover, spatiotemporal gait deficits including cadence, cycle time, step time, swing percent of cycle, stride length, and changes in relative mean pressure were less severe post-stroke in Tan IIA-NP treated pigs relative to control pigs. Conclusion The findings of this proof of concept study strongly suggest that administration of Tan IIA-NPs in the acute phase post-stroke mitigates neural injury likely through limiting free radical formation, thus leading to less severe gait deficits in a translational pig ischemic stroke model. With stroke as one of the leading causes of functional disability in the United States, and gait deficits being a major component, these promising results suggest that acute Tan IIA-NP administration may improve functional outcomes and the quality of life of many future stroke patients., Highlights • Tanshinone IIA loaded nanoparticles demonstrate antioxidative capabilities in neural stem cell cultures. • Tanshinone IIA loaded nanoparticles leads to reduced lesion volume, midline shift, and white matter damage post-stroke. • Tanshinone IIA loaded nanoparticle treatment leads to marked improvements in spatiotemporal and kinetic gait parameters.

Highlights • There are no quantitative markers of major depression that associates with brain. • Switching strategy during verbal fluency can be calculated via machine learning. • Switching between semantic clusters is related to cognitive function in depression. • It is associated with cortical thickness in frontal, temporal and occipital regions. • It is associated with fractional anisotropy in right long antero-posterior tracts., Background The search of biomarkers in the field of depression requires easy implementable tests that are biologically rooted. Qualitative analysis of verbal fluency tests (VFT) are good candidates, but its cerebral correlates are unknown. Methods We collected qualitative semantic and phonemic VFT scores along with grey and white matter anatomical MRI of depressed (n = 26) and healthy controls (HC, n = 25) women. Qualitative VFT variables are the “clustering score” (i.e. the ability to produce words within subcategories) and the “switching score” (i.e. the ability to switch between clusters). The clustering and switching scores were automatically calculated using a data-driven approach. Brain measures were cortical thickness (CT) and fractional anisotropy (FA). We tested for associations between CT, FA and qualitative VFT variables within each group. Results Patients had reduced switching VFT scores compared to HC. Thicker cortex was associated with better switching score in semantic VFT bilaterally in the frontal (superior, rostral middle and inferior gyri), parietal (inferior parietal lobule including the supramarginal gyri), temporal (transverse and fusiform gyri) and occipital (lingual gyri) lobes in the depressed group. Positive association between FA and the switching score in semantic VFT was retrieved in depressed patients within the corpus callosum, right inferior fronto-occipital fasciculus, right superior longitudinal fasciculus extending to the anterior thalamic radiation (all p

Children with a fetal alcohol spectrum disorder (FASD) experience a range of cognitive and behavioral effects. Prior studies have demonstrated white matter changes in children with FASD relative to typically developing controls (TDC) and these changes relate to behavior. Our prior MEG study (Candelaria-Cook et al. 2020) demonstrated reduced alpha oscillations during rest in FASD relative to TDC and alpha power is correlated with behavior. However, little is known about how brain structure influences brain function. We hypothesized that alpha power was related to corticothalamic connectivity. Children 8–13 years of age (TDC: N = 25, FASD: N = 24) underwent rest MEG with eyes open or closed and MRI to collect structural and diffusion tensor imaging data. MEG spectral analysis was performed for sensor and source data. We estimated mean fractional anisotropy in regions of interest (ROIs) that included the corticothalamic tracts. The FASD group had reduced mean FA in three of the corticothalamic ROIs. FA in these tracts was significantly correlated with alpha power at the sensor and source level. The results support the hypothesis that integrity of the corticothalamic tracts influences cortical alpha power. Further research is needed to understand how brain structure and function influence behavior.

Highlights • Covariant abnormalities of GM and WM occurred in SCD and MCI. • GM-WM covariant abnormalities were correlated with cognitive performance in SCD. • Multimodal fusion highlighted the interaction of sMRI and DTI in SCD and MCI., Background Previous multimodal neuroimaging studies analyzed each dataset independently in subjective cognitive decline (SCD) and mild cognitive impairment (MCI), missing the cross-information. Multi-modal fusion analysis can provide more integral and comprehensive information regarding the brain. There has been a paucity of research on fusion analysis of sMRI and DTI in SCD and MCI. Materials and Methods In the present study, we conducted fusion analysis of structural MRI and DTI by applying multimodal canonical correlation analysis with joint independent component analysis (mCCA-jICA) to capture the cross-information of gray matter (GM) and white matter (WM) in 62 SCD patients, 99 MCI patients, and 70 healthy controls (HCs). We further analyzed correlations between the mixing coefficients of mCCA-jICA and neuropsychological scores among the three groups. Results A set of joint-discriminative independent components of GM and fractional anisotropy (FA) exhibited significant links between SCD and HCs, as well as between MCI and HCs. The covariant abnormalities primarily involved the frontal lobe/middle temporal gyrus/calcarine sulcus-anterior thalamic radiation/superior longitudinal fasciculus in SCD, and middle temporal gyrus/ fusiform gyrus/caudate necleus-forceps minor/anterior thalamic radiation in MCI. There was no significant difference between SCD and MCI groups. Conclusions The covariant GM-WM abnormalities in SCD and MCI were found in specific brain regions involved in cognitive processing, which confirms the simultaneous GM and WM changes underlying cognitive decline. These findings suggest that multimodal fusion analysis allows for a more comprehensive understanding of the association among different types of brain tissues and its crucial role in the neuropathological mechanism of SCD and MCI.

Highlights • Gait and balance impairments correlated to various imaging abnormalities. • Stride length, cadence and balance varied independently in PSP. • PSP phenotype affects the associations between gait and imaging., Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET uptake in the left paracentral lobule and supplementary motor area and white matter disruption in the superior cerebellar peduncle, putamen, pontine crossing tract and corticospinal tract. A partial least square model identified flortaucipir-PET uptake in midbrain, basal ganglia and thalamus as the main correlate of speed and dynamic component of gait in progressive supranuclear palsy. Although causality cannot be established in this analysis, our study sheds light on neurodegeneration of brain regions and white matter tracts that underlies gait and balance impairment in progressive supranuclear palsy.

Graphical abstract, Highlights • Putamen susceptibility value was higher in PD than controls one year into diagnosis. • Putamen susceptibility value was associated with clinical motor scores in early PD. • Mean diffusivity revealed greater cellular loss in the lateral substantial nigra. • Putamen and caudate microstructural degradation were driven by radial diffusivity. • A composite putamen-caudate DKI-QSM marker classified early PD from controls., Objective To investigate the utility of quantitative susceptibility mapping (QSM) and diffusion kurtosis imaging (DKI) as complementary tools in characterizing pathological changes in the deep grey nuclei in early Parkinson’s disease (PD) and their clinical correlates to aid in diagnosis of PD. Method Patients with a diagnosis of PD made within a year and age-matched healthy controls were recruited. All participants underwent clinical evaluation using the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS III) and Hoehn & Yahr stage (H&Y), and brain 3 T MRI including QSM and DKI. Regions-of-interest (ROIs) in the caudate nucleus, putamen, globus pallidus, and medial and lateral substantia nigra (SN) were manually drawn to compare the mean susceptibility (representing iron deposition) and DKI indices (representing restricted water diffusion) between PD patients and healthy controls and in correlation with MDS-UPDRS III and H&Y, focusing on susceptibility value, mean diffusivity (MD) and mean kurtosis (MK). Results There were forty-seven PD patients (aged 68.7 years, 51% male, disease duration 0.78 years) and 16 healthy controls (aged 67.4 years, 63% male). Susceptibility value was increased in PD in all ROIs except the caudate, and was significantly different after multiple comparison correction in the putamen (PD: 64.75 ppb, HC: 44.61 ppb, p = 0.004). MD was significantly higher in PD in the lateral SN, putamen and caudate, the regions with the lowest susceptibility value. In PD patients, we found significant association between the MDS-UPDRS III score and susceptibility value in the putamen after correcting for age and sex (β = 0.21, p = 0.003). A composite DKI-QSM diagnostic marker based on these findings successfully differentiated the groups (p

Highlights • Cases were children cooled for neonatal encephalopathy, without cerebral palsy. • Controls were matched for age, sex and socioeconomic status. • In cases, tract-level fractional anisotropy correlated with motor performance. • Graph-theoretic properties of structural networks correlated with motor performance. • Connections to frontal lobe regions were associated with motor performance., Therapeutic hypothermia reduces the incidence of severe motor disability, such as cerebral palsy, following neonatal hypoxic-ischaemic encephalopathy. However, cooled children without cerebral palsy at school-age demonstrate motor deficits and altered white matter connectivity. In this study, we used diffusion-weighted imaging to investigate the relationship between white matter connectivity and motor performance, measured using the Movement Assessment Battery for Children-2, in children aged 6–8 years treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy at birth, who did not develop cerebral palsy (cases), and matched typically developing controls. Correlations between total motor scores and diffusion properties in major white matter tracts were assessed in 33 cases and 36 controls. In cases, significant correlations (FDR-corrected P

Highlights • Tensor-valued dMRI facilitates prediction of meningioma consistency, grade and type. • Tensor-valued dMRI corroborates findings of diffusion tensor and kurtosis imaging. • MK and MKA is associated with firm and MD with variable meningioma consistency. • Variability of MKI in the vicinity of the tumor is associated with meningioma grade. • MKA 50 and MKI 50 separates psammomatous meningiomas from other meningioma types., Background Preoperative radiological assessment of meningioma characteristics is of value for pre- and post-operative patient management, counselling, and surgical approach. Purpose To investigate whether tensor-valued diffusion MRI can add to the preoperative prediction of meningioma consistency, grade and type. Materials and methods 30 patients with intracranial meningiomas (22 WHO grade I, 8 WHO grade II) underwent MRI prior to surgery. Diffusion MRI was performed with linear and spherical b-tensors with b-values up to 2000 s/mm2. The data were used to estimate mean diffusivity (MD), fractional anisotropy (FA), mean kurtosis (MK) and its components—the anisotropic and isotropic kurtoses (MKA and MKI). Meningioma consistency was estimated for 16 patients during resection based on ultrasonic aspiration intensity, ease of resection with instrumentation or suction. Grade and type were determined by histopathological analysis. The relation between consistency, grade and type and dMRI parameters was analyzed inside the tumor (“whole-tumor”) and within brain tissue in the immediate periphery outside the tumor (“rim”) by histogram analysis. Results Lower 10th percentiles of MK and MKA in the whole-tumor were associated with firm consistency compared with pooled soft and variable consistency (n = 7 vs 9; U test, p = 0.02 for MKA 10 and p = 0.04 for MK10) and lower 10th percentile of MD with variable against soft and firm (n = 5 vs 11; U test, p = 0.02). Higher standard deviation of MKI in the rim was associated with lower grade (n = 22 vs 8; U test, p = 0.04) and in the MKI maps we observed elevated rim-like structure that could be associated with grade. Higher median MKA and lower median MKI distinguished psammomatous type from other pooled meningioma types (n = 5 vs 25; U test; p = 0.03 for MKA 50 and p = 0.03 and p = 0.04 for MKI 50). Conclusion Parameters from tensor-valued dMRI can facilitate prediction of consistency, grade and type.

Background: To develop and validate a deep learning signature (DLS) from diffusion tensor imaging (DTI) for predicting overall survival in patients with infiltrative gliomas, and to investigate the biological pathways underlying the developed DLS. Methods: The DLS was developed based on a deep learning cohort (n = 688). The key pathways underlying the DLS were identified on a radiogenomics cohort with paired DTI and RNA-seq data (n=78), where the prognostic value of the pathway genes was validated in public databases (TCGA, n = 663; CGGA, n = 657). Findings: The DLS was associated with survival (log-rank P < 0.001) and was an independent predictor (P < 0.001). Incorporating the DLS into existing risk system resulted in a deep learning nomogram predicting survival better than either the DLS or the clinicomolecular nomogram alone, with a better calibration and classification accuracy (net reclassification improvement 0.646, P < 0.001). Five kinds of pathways (synaptic transmission, calcium signaling, glutamate secretion, axon guidance, and glioma pathways) were significantly correlated with the DLS. Average expression value of pathway genes showed prognostic significance in our radiogenomics cohort and TCGA/CGGA cohorts (log-rank P < 0.05). Interpretation: DTI-derived DLS can improve glioma stratification by identifying risk groups with dysregulated biological pathways that contributed to survival outcomes. Therapies inhibiting neuron-to-brain tumor synaptic communication may be more effective in high-risk glioma defined by DTI-derived DLS. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Highlights • BMI was associated with widespread structural differences in cortical thickness, surface area, subcortical gray matter volumes and in white matter estimates of fractional anisotropy and mean diffusivity. • BMI was also associated with altered resting-state functional connectivity and working memory during an EN-back task but, contrary to some extant findings, was not related to reward or inhibitory control (as assessed by the Monetary Incentive Delay task and Stop Signal Task). • Excessive weight gain (i.e., more than 20 pounds in a year) was associated at baseline with thicker cortices, and differences in surface area and white matter in regions associated with attention and appetite control (e.g., insula, parahippocampal gyrus), but no functional associations were observed. • All analyses quantified generalizability to an unseen test set. • These findings suggest that brain structure, resting state and working memory are associated with current weight and that brain structure may have potential as an MRI biomarker to identify children at risk for pathological weight gain., Multimodal neuroimaging assessments were utilized to identify generalizable brain correlates of current body mass index (BMI) and predictors of pathological weight gain (i.e., beyond normative development) one year later. Multimodal data from children enrolled in the Adolescent Brain Cognitive Development Study® at 9-to-10-years-old, consisted of structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), resting state (rs), and three task-based functional (f) MRI scans assessing reward processing, inhibitory control, and working memory. Cross-validated elastic-net regression revealed widespread structural associations with BMI (e.g., cortical thickness, surface area, subcortical volume, and DTI), which explained 35% of the variance in the training set and generalized well to the test set (R2 = 0.27). Widespread rsfMRI inter- and intra-network correlations were related to BMI (R2train = 0.21; R2test = 0.14), as were regional activations on the working memory task (R2train = 0.20; (R2test = 0.16). However, reward and inhibitory control tasks were unrelated to BMI. Further, pathological weight gain was predicted by structural features (Area Under the Curve (AUC)train = 0.83; AUCtest = 0.83, p < 0.001), but not by fMRI nor rsfMRI. These results establish generalizable brain correlates of current weight and future pathological weight gain. These results also suggest that sMRI may have particular value for identifying children at risk for pathological weight gain.

Graphical abstract, Highlights • FBA shows greater specificity in mapping injured fibers in post-stroke aphasia. • Intra-axonal volume of axons in dual streams is reduced in post-stroke aphasia. • FBA could locate more precise segments associated with language defects. • FBA could attribute language subdomain scores to fiber density of distinct tracts., Background The complex crossing-fiber characteristics in the dual-stream system have been ignored by traditional diffusion tensor models regarding disconnections in post-stroke aphasia. It is valuable to identify microstructural damage of crossing-fiber pathways and reveal accurate fiber-specific language mapping in patients with aphasia. Methods This cross-sectional study collected magnetic resonance imaging data from 29 participants with post-stroke aphasia in the subacute stage and from 33 age- and sex-matched healthy controls. Fixel-based analysis was performed to examine microstructural fiber density (FD) and bundle cross-section alterations of specific fiber populations in crossing-fiber regions. Group comparisons were performed, and relationships with language scores were assessed. Results The aphasic group exhibited significant fixel-wise FD reductions in the dual-stream tracts, including the left inferior fronto-occipital fasciculus (IFOF), arcuate fasciculus, and superior longitudinal fasciculus (SLF) III (family-wise-error-corrected p

Graphical abstract, Highlights • We studied brain structure in case children cooled for neonatal encephalopathy. • Cases did not have cerebral palsy and were matched with controls. • Cases had reduced fractional anisotropy in several white matter tracts. • Several whole-brain structural connectivity network metrics correlated with IQ. • We identified subnetworks associated with case status, IQ and processing speed., Therapeutic hypothermia following neonatal encephalopathy due to birth asphyxia reduces death and cerebral palsy. However, school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy still have reduced performance on cognitive and motor tests, attention difficulties, slower reaction times and reduced visuo-spatial processing abilities compared to typically developing controls. We acquired diffusion-weighted imaging data from school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal encephalopathy at birth, and a matched control group. Voxelwise analysis (33 cases, 36 controls) confirmed reduced fractional anisotropy in widespread areas of white matter in cases, particularly in the fornix, corpus callosum, anterior and posterior limbs of the internal capsule bilaterally and cingulum bilaterally. In structural brain networks constructed using probabilistic tractography (22 cases, 32 controls), graph-theoretic measures of strength, local and global efficiency, clustering coefficient and characteristic path length were found to correlate with IQ in cases but not controls. Network-based statistic analysis implicated brain regions involved in visuo-spatial processing and attention, aligning with previous behavioural findings. These included the precuneus, thalamus, left superior parietal gyrus and left inferior temporal gyrus. Our findings demonstrate that, despite the manifest successes of therapeutic hypothermia, brain development is impaired in these children.

Highlights • Bulbar symptom onset shows more structural impairment than limb-onset in ALS. • Bulbar-onset ALS is characterized by an early and widespread cortical pathology. • Application of the D50 model enables comparability of heterogenous patient cohorts., Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by a high heterogeneity in patients’ disease course. Patients with bulbar onset of symptoms (b-ALS) have a poorer prognosis than patients with limb onset (l-ALS). However, neuroimaging correlates of the assumed biological difference between b-ALS and l-ALS may have been obfuscated by patients’ diversity in the disease course. We conducted Voxel-Based-Morphometry (VBM) and Tract-Based-Spatial-Statistics (TBSS) in a group of 76 ALS patients without clinically relevant cognitive deficits. The subgroups of 26 b-ALS and 52 l-ALS patients did not differ in terms of disease Phase or disease aggressiveness according to the D50 progression model. VBM analyses showed widespread ALS-related changes in grey and white matter, that were more pronounced for b-ALS. TBSS analyses revealed that b-ALS was predominantly characterized by frontal fractional anisotropy decreases. This demonstrates a higher degree of neurodegenerative burden for the group of b-ALS patients in comparison to l-ALS. Correspondingly, higher bulbar symptom burden was associated with right-temporal and inferior-frontal grey matter density decreases as well as fractional anisotropy decreases in inter-hemispheric and long association tracts. Contrasts between patients in Phase I and Phase II further revealed that b-ALS was characterized by an early cortical pathology and showed a spread only outside primary motor regions to frontal and temporal areas. In contrast, l-ALS showed ongoing structural integrity loss within primary motor-regions until Phase II. We therefore provide a strong rationale to treat both onset types of disease separately in ALS studies.

Background: White matter (WM) impairment is a hallmark of amyotrophic lateral sclerosis (ALS). This study evaluated the capacity of mean apparent propagator magnetic resonance imaging (MAP-MRI) for detecting ALS-related WM alterations. Methods: Diffusion images were obtained from 52 ALS patients and 51 controls. MAP-derived indices [return-to-origin/-axis/-plane probability (RTOP/RTAP/RTPP) and non-Gaussianity (NG)/perpendicular/parallel NG (NG⊥/NG||)] were computed. Measures from diffusion tensor/kurtosis imaging (DTI/DKI) and neurite orientation dispersion and density imaging (NODDI) were also obtained. Voxel-wise analysis (VBA) was performed to determine differences in these parameters. Relationship between MAP parameters and disease severity (assessed by the revised ALS Functional Rating Scale (ALSFRS-R)) was evaluated by Pearson’s correlation analysis in a voxel-wise way. ALS patients were further divided into two subgroups: 29 with limb-only involvement and 23 with both bulbar and limb involvement. Subgroup analysis was then conducted to investigate diffusion parameter differences related to bulbar impairment. Results: The VBA (with threshold of P

Highlights • Cohort study of neonatal encephalopathy using continuous glucose monitoring. • Higher glucose on day 1 associated with widespread changes in brain microstructure. • Lower glucose not associated with brain microstructural changes. • No changes in MR spectroscopy found related to higher or lower glucose., Objective To identify how alterations in glucose levels are associated with regional brain injury in neonatal encephalopathy. Methods This was a prospective cohort study of 102 newborns with neonatal encephalopathy, with continuous glucose monitoring for 72 h. 97 (95%) completed 72 h of therapeutic hypothermia. Brain imaging around day 5 of life included diffusion tensor imaging and MR spectroscopy. Regions of interest were placed for both DTI and MR spectroscopy, and tractography of the optic radiation and corticospinal tract were evaluated. Linear regression models related each MR metric with minimum and maximum glucose values during each day of life, adjusting for 5-minute Apgar scores and umbilical artery pH. Results Higher maximum glucose levels on the first day of life were associated with widespread changes in mean diffusivity in the anterior and posterior white matter, splenium of the corpus callosum, lentiform nucleus, pulvinar nucleus of the thalamus, posterior limb of the internal capsule, and optic radiations, thus including regions traditionally associated with hypoxia–ischemia or hypoglycemia. No associations were found between lower minimum glucose levels and DTI changes in any regions tested, or between glucose levels and MR spectroscopy. Conclusions In this cohort of neonatal encephalopathy with therapeutic hypothermia, higher maximal glucose on the first day of life was associated with widespread microstructural changes, but lower minimum glucose levels were not associated with changes in any of the regions tested. Long-term follow-up will determine if imaging findings translate to long-term outcomes.

Highlights • LGN correlates with structural markers of the anterior and posterior visual pathway. • LGN volume may reduce after an episode of ON, shown in four patients. • LGN volume does not change over time in the absence of ON episodes. • Our findings argue against occult neurodegeneration in the visual pathway in NMO., Objectives Lateral geniculate nucleus (LGN) volume is reduced after optic neuritis (ON) in neuromyelitis optica spectrum disorders (NMOSD). We aimed at a longitudinal assessment of LGN volume in NMOSD. Methods Twenty-nine patients with aquaporin 4-IgG seropositive NMOSD (age: 47.8 ± 14.6 years (y), female: n = 27, history of ON (NMO-ON): n = 17, median time since ON: 3[1.2–12.1]y) and 18 healthy controls (HC; age: 39.3 ± 15.8y; female: n = 13) were included. Median follow-up was 4.1[1.1–4.7]y for patients and 1.7[0.9–3.2]y for HC. LGN volume was measured using a multi-atlas-based approach of automated segmentation on 3 Tesla magnetic resonance images. Retinal optical coherence tomography and probabilistic tractography of the optic radiations (OR) were also performed. Results At baseline, NMO-ON patients had lower LGN volumes (395.4 ± 48.9 mm3) than patients without ON (NMO-NON: 450.7 ± 55.6 mm3; p = 0.049) and HC (444.5 ± 61.5 mm3, p = 0.025). LGN volume was associated with retinal neuroaxonal loss and microstructural OR damage. Longitudinally, there was no change in LGN volumes in the absence of ON, neither in all patients (B = −0.6, SE = 1.4, p = 0.670), nor in NMO-ON (B = −0.8, SE = 1.6, p = 0.617) and NMO-NON (B = 1.7, SE = 3.5, p = 0.650). However, in four patients with new ON during follow-up, LGN volume was reduced at last visit (median time since ON: 2.6 [1.8–3.9] y) compared to the measurement before ON (352 ± 52.7 vs. 371.1 ± 55.9 mm3; t = −3.6, p = 0.036). Conclusion Although LGN volume is reduced after ON in NMOSD, this volume loss is not progressive over longer follow-up or independent of ON. Thus, our findings -at least in this relatively small cohort- do not support occult neurodegeneration of the afferent visual pathway in NMOSD.

Highlights • In aMCI, apathy severity was associated with lower FA in widespread WM pathways. • WM aberrations are related to apathy severity after controlling for depression. • Disruptions related to apathy severity are not limited to frontal-subcortical area., Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer’s Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p

Highlights • ACEs and PTSS did not significantly differ between patients and healthy controls. • Patients demonstrated greater corticolimbic connectivity compared to controls. • Greater PTSS and less corticolimbic connectivity increased headache frequency. • Less corticolimbic connectivity may indicate greater disease progression. • Patients may be more vulnerable to the effects of PTSS compared to controls., Background/aims Post-traumatic stress symptoms (PTSS) and chronic pain often co-occur at high rates in youth. PTSS may alter brain structure thereby contributing to headache chronicity. This study examined whether PTSS and altered limbic circuitry were associated with headache frequency in youth. Methods Thirty youth aged 10–18 years with chronic headaches and 30 age- and sex-matched controls underwent a 3T MRI scan. Volumes of the hippocampus and amygdala were obtained from T1-weighted images. Mean fractional anisotropy (FA, an index of white matter structure) axial and radial diffusivity values of the cingulum and uncinate fasciculus were extracted from diffusion-weighted images. Youth reported on their headaches daily, for one-month, and self-reported pubertal status, emotion regulation, adverse childhood experiences (ACEs) and PTSS using validated measures. Volumes of the hippocampus and amygdala and diffusivity values of the cingulum and uncinate were compared between patients and controls. Hierarchical linear regressions were used to examine the association between PTSS, subcortical volumes and/or diffusivity values and headache frequency. Results Mean FA values of the cingulum were higher in patients compared to controls (P = 0.02, Cohen’s d = 0.69). Greater PTSS (P = 0.04), smaller amygdala volumes (P = 0.01) and lower FA of the cingulum (P = 0.04) were associated with greater headache frequency, after accounting for age, puberty, pain duration, emotion regulation, and ACEs (Adjusted R2 ≥ 0.15). Headache frequency was associated with increases in radial diffusivity (P = 0.002, Adjusted R2 = 0.59), as opposed to axial diffusivity (n.s.). Conclusions PTSS, smaller amygdalar volume, and poorer cingulum structural connectivity were associated with headache frequency in youth, and may underlie headache chronicity.

Highlights • CMC is weaker and occurs at lower frequencies in acute stroke patients. • Both afferent and efferent input signals contribute to CMC. • CMC should not be used as a direct measure of corticospinal tract integrity., In healthy subjects, motor cortex activity and electromyographic (EMG) signals from contracting contralateral muscle show coherence in the beta (15–30 Hz) range. Corticomuscular coherence (CMC) is considered a sign of functional coupling between muscle and brain. Based on prior studies, CMC is altered in stroke, but functional significance of this finding has remained unclear. Here, we examined CMC in acute stroke patients and correlated the results with clinical outcome measures and corticospinal tract (CST) integrity estimated with diffusion tensor imaging (DTI). During isometric contraction of the extensor carpi radialis muscle, EMG and magnetoencephalographic oscillatory signals were recorded from 29 patients with paresis of the upper extremity due to ischemic stroke and 22 control subjects. CMC amplitudes and peak frequencies at 13–30 Hz were compared between the two groups. In the patients, the peak frequency in both the affected and the unaffected hemisphere was significantly (p

Objectives To investigate the relationship between bimanual performance deficits measured using kinematics and callosum (CC) white matter changes that occur in people with chronic stroke. Design Cross-sectional, observational study of participants with chronic stroke and age-matched controls. Setting Recruitment and assessments occurred at a stroke recovery research center. Behavioral assessments were performed in a controlled laboratory setting. Magnetic resonance imaging scans were performed at the Center for Biomedical Imaging. Participants Individuals were enrolled and completed the study (N=39; 21 participants with chronic stroke; 18 age-matched controls with at least 2 stroke risk factors). Main Outcome Measures Diffusion imaging metrics were obtained for each individual’s CC and corticospinal tract (CST), including mean kurtosis (MK) and fractional anisotropy (FA). A battery of motor assessments, including bimanual kinematics, were collected from individuals while performing bimanual reaching. Results Participants with stroke had lower FA and MK in the CST of the lesioned hemisphere when compared with the non-lesioned hemisphere. The FA and MK values in the CST were correlated with measures of unimanual hand performance. In addition, participants with stroke had significantly lower FA and MK in the CC than matched controls. CC diffusion metrics positively correlated with hand asymmetry and trunk displacement during bimanual performance, even when correcting for age and lesion volume. Conclusions These data confirm previous studies that linked CST integrity to unimanual performance and provide new data demonstrating a link between CC integrity and both bimanual motor deficits and compensatory movements., Highlights • Fractional anisotropy and mean kurtosis in the corpus callosum are lower in participants with stroke. • Hand position symmetry and trunk displacement are disrupted during bimanual tasks. • Corpus callosum white matter correlated with bimanual kinematics in participants with stroke.

Highlights • DTI study reveals brain-wide differences between SCA7 patients and controls. • DTI dual-compartment model controls for increased CSF-like free water in patients. • Tensor-based deformations show SCA7 tissue loss extends beyond cerebellum. • Focal atrophy, but global microstructural abnormalities were observed in SCA7., Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. We aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. While common structural MRI techniques have been previously used for this purpose, they can be biased by neurodegeneration-driven increases in extracellular CSF-like water. In a cross-sectional study, we analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and major motor white matter tracts in patients (p 1), pMD and pFA detected microstructural abnormalities in virtually all tissues brain-wide (p 1). The Scale for the Assessment and Rating of Ataxia trended towards correlation with cerebellar pVF (r = −0.66, p = 0.104, FDR corrected) and global white matter pFA (r = −0.64, p = 0.104, FDR corrected). These results advance our understanding of neurodegeneration in living SCA7 patients by providing the first voxel-wise characterization of white matter volume loss and gray matter microstructural abnormalities. Moving forward, this comprehensive approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

Highlights • LHON patients suffered large-scale structural network disruption. • Non-rich club connections may be more vulnerable in the LHON. • Both primary and secondary connectivity damage may coexist in the LHON., Objective The purpose of this study was to investigate whether the large-scale structural rich club organization was abnormal in patients with Leber's hereditary optic neuropathy (LHON) using diffusion tensor imaging (DTI), and the associations among disrupted brain structural connectivity, disease duration, and neuro-ophthalmological impairment. Methods Nineteen acute, 34 chronic LHON patients, and 36 healthy controls (HC) underwent DTI and neuro-ophthalmological measurements. The brain structural network and rich club organization were constructed based on deterministic fiber tracking at the individual level. Then intergroup differences among the acute, chronic LHON patients and healthy controls (HC) in three types of structural connections, including rich club, feeder, and local ones, were compared. Network-based Statistics (NBS) was also used to test the intergroup connectivity differences for each fiber. Several linear and nonlinear curve fit models were applied to explore the associations among large-scale brain structural connectivity, disease duration, and neuro-ophthalmological metrics. Results Compared to the HC, both the acute and chronic LHON patients had consistently significantly lower fractional anisotropy (FA) and higher radial diffusion (RD) for feeder connections (p 0.05, FDR correction). NBS also identified reduced FA of three feeder connections and five local ones linking visual, auditory, and basal ganglia areas in LHON patients (p 0.05, FDR correction). A significant negative correlation was shown between the retinal nerve fiber layer (RNFL) thickness and disease duration (p

Background: Increasing evidence supported the possible neuro-invasion potential of SARS-CoV-2. However, no studies were conducted to explore the existence of the micro-structural changes in the central nervous system after infection. We aimed to identify the existence of potential brain micro-structural changes related to SARS-CoV-2. Methods: In this prospective study, diffusion tensor imaging (DTI) and 3D high-resolution T1WI sequences were acquired in 60 recovered COVID-19 patients (56.67% male; age: 44.10 ± 16.00) and 39 age- and sex-matched non-COVID-19 controls (56.41% male; age: 45.88 ± 13.90). Registered fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were quantified for DTI, and an index score system was introduced. Regional volumes derived from Voxel-based Morphometry (VBM) and DTI metrics were compared using analysis of covariance (ANCOVA). Two sample t-test and Spearman correlation were conducted to assess the relationships among imaging indices, index scores and clinical information. Findings: In this follow-up stage, neurological symptoms were presented in 55% COVID-19 patients. COVID-19 patients had statistically significantly higher bilateral gray matter volumes (GMV) in olfactory cortices, hippocampi, insulas, left Rolandic operculum, left Heschl's gyrus and right cingulate gyrus and a general decline of MD, AD, RD accompanied with an increase of FA in white matter, especially AD in the right CR, EC and SFF, and MD in SFF compared with non-COVID-19 volunteers (corrected p value

Highlights • Fibre properties derived from fixel-based analysis are sensitive to development. • Age-related patterns are consistent with previous diffusion tensor studies. • Pubertal stage correlates with fibre density and morphology in the right SLF. • Pubertal stage correlates with fibre morphology in the right ILF. • Pubertal progression interacts with age for longitudinal fibre density changes., The pubertal period involves dynamic white matter development. This period also corresponds with rapid gains in higher cognitive functions including attention, as well as increased risk of developing mental health difficulties. This longitudinal study comprised children aged 9–13 years (n = 130). Diffusion magnetic resonance imaging (dMRI) data were acquired (b = 2800s/mm2, 60 directions) at two time-points. We derived measures of fibre density and morphology using the fixel-based analysis framework and performed a tract-based mixed-effects modelling analysis to understand patterns of white matter development with respect to age, sex, pubertal stage, and the change in pubertal stage. We observed significant increases in apparent fibre density across a large number of white matter pathways, including major association and commissural pathways. We observed a linear relationship between pubertal stage and fibre density and morphology in the right superior longitudinal fasciculus, and fibre morphology in the right inferior longitudinal fasciculus. Finally, we report a significant interaction between the change in pubertal stage and age in the development of fibre density, for left-lateralised association tracts. Overall, white matter development across ages 9–13 years involves the expansion of major white matter fibre pathways, with key association pathways linked with pubertal stage.

Human cortical development during the third trimester is characterised by macro- and microstructural changes which are reflected in alterations in diffusion MRI (dMRI) measures, with significant decreases in cortical mean diffusivity (MD) and fractional anisotropy (FA). This has been interpreted as reflecting increased cellular density and dendritic arborisation. However, the fall in FA stops abruptly at 38 weeks post-menstrual age (PMA), and then tends to plateau, while MD continues to fall, suggesting a more complex picture and raising the hypothesis that after this age development is dominated by continuing increase in neural and organelle density rather than alterations in the geometry of dendritic trees. To test this, we used neurite orientation dispersion and density imaging (NODDI), acquiring multi-shell, high angular resolution dMRI and measures of cortical volume and mean curvature in 99 preterm infants scanned between 25 and 47 weeks PMA. We predicted that increased neurite and organelle density would be reflected in increases in neurite density index (NDI), while a relatively unchanging geometrical structure would be associated with constant orientation dispersion index (ODI). As dendritic arborisation is likely to be one of the drivers of gyrification, we also predicted that measures of cortical volume and curvature would correlate with ODI and show slower growth after 38 weeks. We observed a decrease of MD throughout the period, while cortical FA decreased from 25 to 38 weeks PMA and then increased. ODI increased up to 38 weeks and then plateaued, while NDI rose after 38 weeks. The evolution of ODI correlated with cortical volume and curvature. Regional analysis of cortical microstructure revealed a heterogenous pattern with increases in FA and NDI after 38 weeks confined to primary motor and sensory regions. These results support the interpretation that cortical development between 25 and 38 weeks PMA shows a predominant increase in dendritic arborisation and neurite growth, while between 38 and 47 weeks PMA it is dominated by increasing cellular and organelle density., Graphical abstract Image 1, Highlights • DTI and NODDI cortical measures between 25 and 47 weeks GA • Early cortical changes consistent with dendritic arborisation and neurite growth • After 38 weeks cortical changes consistent with increasing cellular density • Cortical curvature evolves in parallel with dendritic arborisation

Aim and objectives: To study the diagnostic accuracy of Diffusion tensor imaging technique in detection of cervical spondylotic myelopathy changes. Material and method: Study population included 50 patients with symptoms of cervical myelopathy. The patients were evaluated based on symptoms using the European myelopathy scoring system and were divided into: Grade 1, including patients with mild symptoms; Grade 2, referring to patients with moderate symptoms and Grade 3, which included patients revealing severe symptoms. All the patients were investigated with a 1.5 T MRI unit acquiring DWI and DTI sequences. FA and ADC values from each spinal segment were analyzed in terms of Frequency, Percentage, Mean, Standard Deviation and Confidence Intervals. The comparison of values was done by ANOVA and post hoc analysis by bonferroni test. Comparison of accuracy of FA, ADC and T2WI in recognizing myelopathic changes was done by t-test. Receiver Operating Characteristics (ROC) analysis was performed to obtain a cut off value of FA and ADC for each spinal level to identify myelopathic change in the spinal cord. Results: The study revealed a significant difference in the mean FA and ADC value of stenotic and Non-stenotic segments. T2WI was highly significant (p = 0.000) in recognizing myelopathy changes in patients falling under Grade 2(moderate) and Grade 3(severe) according to European Myelopathy scoring system. Regarding patients under Grade 1 (mild) FA and ADC values showed significant difference compared to T2WI. The collective sensitivity in the identification of myelopathic changes was highest with FA (79%) as compared to ADC (71%) and T2WI (50%). ROC analysis was done to determine the cut off values of FA and ADC at each cervical spine segments. The proposed cut off, for FA and ADC at the level of C1–C2 is 0.68 and 0.92, C2–C3 is 0.65 and 1.03, C3–C4 is 0.63 and 1.01, C4–C5 0.61 and 0.98, At C5–C6 0.57 and 1.04, At C6–C7 0.56 and 0.96 respectively. Conclusion: FA and ADC values enhance the efficacy and accuracy of MRI in the diagnosis of cervical spondylotic myelopathy. Hence diffusion tensor imaging can be used as a non-invasive modality to recognize spondylotic myelopathy changes even in the early stages, which can be helpful in deciding on appropriate timing of decompression surgery before the irreversible chronic changes set in. Keywords: Diffusion tensor imaging, Cervical spondylotic myelopathy

Highlights • Preterm infant white matter tracts uniquely predict later toddler language. • Neonatal medical history moderates posterior corpus callosum–language relations. • Different associations by tract may relate to brain maturation and medical history., Aim To determine whether variability in diffusion MRI (dMRI) white matter tract metrics, obtained in a cohort of preterm infants prior to neonatal hospital discharge, would be associated with language outcomes at age 2 years, after consideration of age at scan and number of major neonatal complications. Method 30 children, gestational age 28.9 (2.4) weeks, underwent dMRI at mean post menstrual age 36.4 (1.4) weeks and language assessment with the Bayley Scales of Infant Development–III at mean age 22.2 (1.7) months chronological age. Mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated for 5 white matter tracts. Hierarchical linear regression assessed associations between tract FA, moderating variables, and language outcomes. Results FA of the left inferior longitudinal fasciculus accounted for 17% (p = 0.03) of the variance in composite language and FA of the posterior corpus callosum accounted for 19% (p = 0.02) of the variance in composite language, beyond that accounted for by post-menstrual age at scan and neonatal medical complications. The number of neonatal medical complications moderated the relationship between language and posterior corpus callosum FA but did not moderate the association in the other tract. Conclusion Language at age 2 is associated with white matter metrics in early infancy in preterm children. The different pattern of associations by fiber group may relate to the stage of brain maturation and/or the nature and timing of medical complications related to preterm birth. Future studies should replicate these findings with a larger sample size to assure reliability of the findings.

Highlights • Brain (micro-)structural differences were found in pre-adolescents who stutter. • Persistency was associated with marginally smaller left frontal gray matter volume. • Recovery was associated with higher mean diffusivity in white matter tracts. • Distinct brain structures implicated in persistence and recovery of stuttering., Background Stuttering is a complex speech fluency disorder occurring in childhood. In young children, stuttering has been associated with speech-related auditory and motor areas of the brain. During transition into adolescence, the majority of children who stutter (75–80%) will experience remission of their symptoms. The current study evaluated brain (micro-)structural differences between pre-adolescents who persisted in stuttering, those who recovered, and fluently speaking controls. Methods This study was embedded in the Generation R Study, a population-based cohort in the Netherlands of children followed from pregnancy onwards. Neuroimaging was performed in 2211 children (mean age: 10 years, range 8–12), of whom 20 persisted in and 77 recovered from stuttering. Brain structure (e.g., gray matter) and microstructure (e.g., diffusion tensor imaging) differences between groups were tested using multiple linear regression. Results Pre-adolescents who persisted in stuttering had marginally lower left superior frontal gray matter volume compared to those with no history of stuttering (β −1344, 95%CI −2407;-280), and those who recovered (β −1825, 95%CI −2999;-650). Pre-adolescents who recovered, compared to those with no history of stuttering, had higher mean diffusivity in the forceps major (β 0.002, 95%CI 0.001;0.004), bilateral superior longitudinal fasciculi (β 0.001, 95%CI 0.000;0.001), left corticospinal tract (β 0.003, 95%CI 0.002;0.004), and right inferior longitudinal fasciculus (β 0.001, 95%CI 0.000;0.001). Conclusion Findings suggest that relatively small difference in prefrontal gray matter volume is associated with persistent stuttering, and alterations in white matter tracts are apparent in individuals who recovered. The findings further strengthen the potential relevance of brain (micro-)structure in persistence and recovery from stuttering in pre-adolescents.

Background Parkinson's disease (PD) and progressive supranuclear palsy – Richardson's syndrome (PSP-RS) are often represented by similar clinical symptoms, which may challenge diagnostic accuracy. The objective of this study was to investigate and compare regional cerebral diffusion properties in PD and PSP-RS subjects and evaluate the use of these metrics for an automatic classification framework. Material and methods Diffusion-tensor MRI datasets from 52 PD and 21 PSP-RS subjects were employed for this study. Using an atlas-based approach, regional median values of mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were measured and employed for feature selection using RELIEFF and subsequent classification using a support vector machine. Results According to RELIEFF, the top 17 diffusion values consisting of deep gray matter structures, the brainstem, and frontal cortex were found to be especially informative for an automatic classification. A MANCOVA analysis performed on these diffusion values as dependent variables revealed that PSP-RS and PD subjects differ significantly (p, Highlights • Brain diffusion was compared in progressive supranuclear palsy-Richardson's syndrome (PSP-RS) and Parkinson's disease (PD). • Results show widespread diffusion alterations in PSP-RS compared to PD. • PSP-RS patients show significant reduction of FA and an increase of MD, RD, and AD values in compared to PD. • RELIEFF feature selection combined with a support vector machine classifier resulted in a differentiation accuracy of 87.7%.

Background Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective To evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p, Highlights • We describe a fully-automated optic radiation probabilistic tractography approach (CSD-PROB) that is feasible in healthy controls and patients with neuroimmunological diseases. • We demonstrate CSD-PROB to yield superior sensitivity and specificity in differentiating NMOSD from healthy controls compared to TBSS-based optic radiation ROI methods and ConTrack-based probabilistic tractography. • CSD-PROB shows significant differences between healthy controls and patients with clinically isolated syndrome and early multiple sclerosis without prior optic neuritis. • The comparison of different subject groups by use of different DWI post-processing methods may lead to either false-positive or false-negative results, which may be of particular significance for future optic radiation DTI comparison in studies and meta-analyses.

Background Myocardial disarray is a likely focus for fatal arrhythmia in hypertrophic cardiomyopathy (HCM). This microstructural abnormality can be inferred by mapping the preferential diffusion of water along cardiac muscle fibers using diffusion tensor cardiac magnetic resonance (DT-CMR) imaging. Fractional anisotropy (FA) quantifies directionality of diffusion in 3 dimensions. The authors hypothesized that FA would be reduced in HCM due to disarray and fibrosis that may represent the anatomic substrate for ventricular arrhythmia. Objectives This study sought to assess FA as a noninvasive in vivo biomarker of HCM myoarchitecture and its association with ventricular arrhythmia. Methods A total of 50 HCM patients (47 ± 15 years of age, 77% male) and 30 healthy control subjects (46 ± 16 years of age, 70% male) underwent DT-CMR in diastole, cine, late gadolinium enhancement (LGE), and extracellular volume (ECV) imaging at 3-T. Results Diastolic FA was reduced in HCM compared with control subjects (0.49 ± 0.05 vs. 0.52 ± 0.03; p = 0.0005). Control subjects had a mid-wall ring of high FA. In HCM, this ring was disrupted by reduced FA, consistent with published histology demonstrating that disarray and fibrosis invade circumferentially aligned mid-wall myocytes. LGE and ECV were significant predictors of FA, in line with fibrosis contributing to low FA. Yet FA adjusted for LGE and ECV remained reduced in HCM (p = 0.028). FA in the hypertrophied segment was reduced in HCM patients with ventricular arrhythmia compared to patients without (n = 15; 0.41 ± 0.03 vs. 0.46 ± 0.06; p = 0.007). A decrease in FA of 0.05 increased odds of ventricular arrhythmia by 2.5 (95% confidence interval: 1.2 to 5.3; p = 0.015) in HCM and remained significant even after correcting for LGE, ECV, and wall thickness (p = 0.036). Conclusions DT-CMR assessment of left ventricular myoarchitecture matched patterns reported previously on histology. Low diastolic FA in HCM was associated with ventricular arrhythmia and is likely to represent disarray after accounting for fibrosis. The authors propose that diastolic FA could be the first in vivo marker of disarray in HCM and a potential independent risk factor., Central Illustration

INTRODUCTION: The dynamic nature and complexity of the cellular events that take place during the last trimester of pregnancy make the developing cortex particularly vulnerable to perturbations. Abrupt interruption to normal gestation can lead to significant deviations to many of these processes, resulting in atypical trajectory of cortical maturation in preterm birth survivors. METHODS: We sought to first map typical cortical micro- and macrostructure development using invivo MRI in a large sample of healthy term-born infants scanned after birth (n = 259). Then we offer a comprehensive characterization of the cortical consequences of preterm birth in 76 preterm infants scanned at term-equivalent age (37-44 weeks postmenstrual age). We describe the group-average atypicality, the heterogeneity across individual preterm infants, and relate individual deviations from normative development to age at birth and neurodevelopment at 18 months. RESULTS: In the term-born neonatal brain, we observed heterogeneous and regionally specific associations between age at scan and measures of cortical morphology and microstructure, including rapid surface expansion, greater cortical thickness, lower cortical anisotropy and higher neurite orientation dispersion. By term-equivalent age, preterm infants had on average increased cortical tissue water content and reduced neurite density index in the posterior parts of the cortex, and greater cortical thickness anteriorly compared to term-born infants. While individual preterm infants were more likely to show extreme deviations (over 3.1 standard deviations) from normative cortical maturation compared to term-born infants, these extreme deviations were highly variable and showed very little spatial overlap between individuals. Measures of regional cortical development were associated with age at birth, but not with neurodevelopment at 18 months. CONCLUSION: We showed that preterm birth alters cortical micro- and macrostructural maturation near the time of full-term birth. Deviations from normative development were highly variable between individual preterm infants. ispartof: NEUROIMAGE vol:243 ispartof: location:United States status: published

Highlights • Fronto-temporal white matter tracts relate to social network size. • Specific limbic and temporal regions are larger in people with larger social networks. • Functional coupling of the default mode network varies with social network size., Social skills rely on a specific set of cognitive processes, raising the possibility that individual differences in social networks are related to differences in specific brain structural and functional networks. Here, we tested this hypothesis with multimodality neuroimaging. With diffusion MRI (DMRI), we showed that differences in structural integrity of particular white matter (WM) tracts, including cingulum bundle, extreme capsule and arcuate fasciculus were associated with an individual’s social network size (SNS). A voxel-based morphology analysis demonstrated correlations between gray matter (GM) volume and SNS in limbic and temporal lobe regions. These structural changes co-occured with functional network differences. As a function of SNS, dorsomedial and dorsolateral prefrontal cortex showed altered resting-state functional connectivity with the default mode network (DMN). Finally, we integrated these three complementary methods, interrogating the relationship between social GM clusters and specific WM and resting-state networks (RSNs). Probabilistic tractography seeded in these GM nodes utilized the SNS-related WM pathways. Further, the spatial and functional overlap between the social GM clusters and the DMN was significantly closer than other control RSNs. These integrative analyses provide convergent evidence of the role of specific circuits in SNS, likely supporting the adaptive behavior necessary for success in extensive social environments.

Atrophy of the brain grey matter (GM) is an accepted and important feature of multiple sclerosis (MS). However, its accurate measurement is hampered by various technical, pathological and physiological factors. As a consequence, it is challenging to investigate the role of GM atrophy in the disease process as well as the effect of treatments that aim to reduce neurodegeneration. In this paper we discuss the most important challenges currently hampering the measurement and interpretation of GM atrophy in MS. The focus is on measurements that are obtained in individual patients rather than on group analysis methods, because of their importance in clinical trials and ultimately in clinical care. We discuss the sources and possible solutions of the current challenges, and provide recommendations to achieve reliable measurement and interpretation of brain GM atrophy in MS., Highlights • Accurate measurement of brain GM atrophy in MS is hampered by various physiological, pathological and technical factors. • Challenges to achieve accuracy in quantification and interpretation of atrophy in MS are discussed. • Recommendations on how to achieve reliable measurement and interpretation of GM atrophy in MS are suggested.

Highlights • Estimation of the corticospinal tract in patients with gliomas based on diffusion kurtosis tensor imaging using a 1.5T magnetic field showed similar proprieties as the tracts reconstructed using diffusion tensor tractography., Tractography studies for pre-surgical planning of primary brain tumors is typically done using diffusion tensor imaging (DTI), which cannot resolve crossing, kissing or highly angulated fibres. Tractography based on the estimation of the diffusion kurtosis (DK) tensor was recently demonstrated to enable tackling these limitations. However, its use in the clinical context at low 1.5T field has not yet been reported. Purpose To evaluate if the estimation of whole-brain tractography using the DK tensor is feasible for pre-surgical investigation of patients with brain tumors at 1.5T. Methods Eight healthy subjects and 3 patients with brain tumors were scanned at 1.5T using a 12-channel head coil. Diffusion-weighted images were acquired with repetition/echo times of 5800/107 ms, 82 × 82 resolution, 3 × 3 × 3 mm3 voxel size, b-values of 0, 1000, 2000 s/mm2 and 64 gradient sensitising directions. Whole-brain tractography was estimated using the DK tensor and corticospinal tracts (CST) were isolated using regions-of-interest placed at the cerebral peduncles and motor gyrus. Tract size, DK metrics and CST deviation index (highest curvature point) were compared between healthy subjects and patients. Results Tract sizes did not differ between groups. The CST deviation index was significantly higher in patients compared to healthy subjects. Fractional anisotropy was significantly lower in patients, with higher mean kurtosis asymmetry index at the highest curvature point in patients. Conclusions Corticospinal fibre bundles estimated using DK tensor in a 1.5T scanner presented similar properties in patients with brain gliomas as those reported in the literature using DTI-based tractography.

Objective Repetitive subconcussive head impacts (RSHI) may lead to structural, functional, and metabolic alterations of the brain. While differences between males and females have already been suggested following a concussion, whether there are sex differences following exposure to RSHI remains unknown. The aim of this study was to identify and to characterize sex differences following exposure to RSHI. Methods Twenty-five collegiate ice hockey players (14 males and 11 females, 20.6 ± 2.0 years), all part of the Hockey Concussion Education Project (HCEP), underwent diffusion-weighted magnetic resonance imaging (dMRI) before and after the Canadian Interuniversity Sports (CIS) ice hockey season 2011–2012 and did not experience a concussion during the season. Whole-brain tract-based spatial statistics (TBSS) were used to compare pre- and postseason imaging in both sexes for fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). Pre- and postseason neurocognitive performance were assessed by the Immediate Post-Concussion Assessment and Cognitive Test (ImPACT). Results Significant differences between the sexes were primarily located within the superior longitudinal fasciculus (SLF), the internal capsule (IC), and the corona radiata (CR) of the right hemisphere (RH). In significant voxel clusters (p, Highlights • This study explores sex differences following repetitive subconcussive head impacts. • Decreases in FA were observed in females over the course of one ice hockey season. • Females also showed increases in MD, AD, and RD over the course of the season. • In contrast, males showed no significant changes in these diffusion measures. • The results suggest sex differences in structural alterations following subconcussion.

Objective To determine the relationship between brain tissue metabolites measured by in vivo magnetic resonance spectroscopy (1H-MRS), and glial activation assessed with [11C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS). Methods Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSFRS-R) and upper motor neuron burden (UMNB). All participants underwent simultaneous brain [11C]-PBR28 PET and MR imaging including diffusion tensor imaging to acquire fractional anisotropy (FA). [11C]-PBR28 uptake was measured as standardized uptake values normalized by whole brain mean (SUVR). 1H-MRS metabolite ratios (myo-inositol/creatine, mI/Cr; N-acetylaspartate/creatine, NAA/Cr) were measured within the precentral gyri and brain stem (regions known to be involved in ALS pathophysiology), and precuneus (which served as a control region). Whole brain voxel-wise correlation analyses were employed to identify brain regions exhibiting an association between metabolites within the VOIs and [11C]-PBR28 uptake. Results In the precentral gyri, [11C]-PBR28 uptake correlated positively with mI/Cr and negatively with NAA/Cr. The same correlations were not statistically significant in the brain stem, or in the control precuneus region. Whole brain voxel-wise correlation analyses between the estimated brain metabolites within the VOIs and SUVR were highly correlated in the precentral gyri. Decreased FA values in the precentral gyri were correlated with reduced NAA/Cr and elevated mI/Cr. Higher UMNB was correlated with increased [11C]-PBR28 uptake and mI/Cr, and decreased NAA/Cr. ALSFRS-R total score correlated positively with NAA/Cr and negatively with mI/Cr. Conclusion Integrated PET-MR and 1H-MRS imaging demonstrates associations between markers for neuronal integrity and neuroinflammation and may provide valuable insights into disease mechanisms in ALS., Highlights • This study evaluates the relationship between 1H-MRS and [11C]-PBR28 PET-MR measures in people with ALS. • Myo-inositol/Creatine correlates positively with glial activation measured by [11C]-PBR28 PET, and negatively with fractional anisotropy. • N-acetyl-aspartate/Creatine correlates negatively with [11C]-PBR28 PET, and positively with fractional anisotropy. • Myo-inositol/Creatine and N-acetyl-aspartate/Creatine correlate with ALS-functional rating scale and upper motor neuron burden. • 1H-MRS and PET-MR measures provide complementary information to better understand brain pathology in people with ALS.

Objective Isolated adult-onset focal dystonia is considered a network disorder with disturbances to the motor basal ganglia and cerebellar circuits playing a pathophysiological role, but why specific body regions become affected remains unknown. We aimed to use diffusion tensor imaging to determine if the two most common phenotypes of focal dystonia are associated with distinguishing microstructural changes affecting the motor network. Methods Fifteen blepharospasm patients, 20 cervical dystonia patients, and 30 age- and sex-matched healthy controls were recruited. Maps of fractional anisotropy and mean diffusivity were analyzed using a voxel-based approach and an automated region-of-interest technique to evaluate deep gray matter nuclei. Correlations between diffusion measures and dystonia severity were tested, and post hoc discriminant analyses were conducted. Results Voxel-based analyses revealed significantly reduced fractional anisotropy in the right cerebellum and increased mean diffusivity in the left caudate of cervical dystonia patients compared to controls, as well as lower fractional anisotropy in the right cerebellum in cervical dystonia patients relative to blepharospasm patients. In addition to reduced fractional anisotropy in the bilateral caudate nucleus of cervical dystonia patients relative to controls and blepharospasm patients, region-of-interest analyses revealed significantly reduced fractional anisotropy in the right globus pallidus internus and left red nucleus of blepharospasm patients compared to both controls and cervical dystonia patients. Diffusivity measures in the red nucleus of blepharospasm patients correlated with disease severity. In a three-group discriminant analysis, participants were correctly classified with only modest reliability (67–75%), but in a two-group discriminant analysis, patients could be distinguished from each other with high reliability (83–100%). Conclusions Different focal dystonia phenotypes are associated with distinct patterns of altered microstructure within constituent regions of basal ganglia and cerebellar circuits., Highlights • Globus pallidus and red nucleus microstructure is altered in blepharospasm. • Caudate and cerebellar microstructure is altered in cervical dystonia. • Disease severity in blepharospasm correlates with diffusivity in the red nucleus. • Diffusivity differences can differentiate blepharospasm from cervical dystonia. • Basal ganglia and cerebellar network disruptions may differ in dystonia phenotypes.

Background Despite recent advances in diffusion MRI (dMRI), there is still limited information on neurite orientation dispersion and density imaging (NODDI) in temporal lobe epilepsy (TLE). This study aimed to demonstrate neurite density and dispersion in TLE with and without hippocampal sclerosis (HS) using whole-brain voxel-wise analyses. Material and methods We recruited 33 patients with unilateral TLE (16 left, 17 right), including 14 patients with HS (TLE-HS) and 19 MRI-negative 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)-positive patients (MRI-/PET+ TLE). The NODDI toolbox calculated the intracellular volume fraction (ICVF) and orientation dispersion index (ODI). Conventional dMRI metrics, that is, fractional anisotropy (FA) and mean diffusivity (MD), were also estimated. After spatial normalization, all dMRI parameters (ICVF, ODI, FA, and MD) of the patients were compared with those of age- and sex-matched healthy controls using Statistical Parametric Mapping 12 (SPM12). As a complementary analysis, we added an atlas-based region of interest (ROI) analysis of relevant white matter tracts using tract-based spatial statistics. Results We found decreased neurite density mainly in the ipsilateral temporal areas of both right and left TLE, with the right TLE showing more severe and widespread abnormalities. In addition, etiology-specific analyses revealed a localized reduction in ICVF (i.e., neurite density) in the ipsilateral temporal pole in MRI-/PET+ TLE, whereas TLE-HS presented greater abnormalities, including FA and MD, in addition to a localized hippocampal reduction in ODI. The results of the atlas-based ROI analysis were consistent with the results of the SPM12 analysis. Conclusion NODDI may provide clinically relevant information as well as novel insights into the field of TLE. Particularly, in MRI-/PET+ TLE, neurite density imaging may have higher sensitivity than other dMRI parameters. The results may also contribute to better understanding of the pathophysiology of TLE with HS., Highlights • We examined temporal lobe epilepsy (TLE) with or without hippocampal sclerosis (HS). • Neurite orientation dispersion and density imaging (NODDI) was used. • Ipsilateral reduction of neurite density was found in MRI-negative PET-positive TLE. • More extensive abnormalities were presented in TLE with HS. • NODDI may provide clinical relevance and novel insights into the field of TLE.

Previous studies reported that the volume of the left superior temporal gyrus (STG) is reduced in patients with schizophrenia and negatively correlated with hallucination severity. Moreover, diffusion-tensor imaging studies suggested a relationship between the brain microstructure in the STG of patients and auditory hallucinations. Hallucinations are also experienced in non-patient groups. This study investigated the relationship between hallucination proneness and the brain structure of the STG. Hallucination proneness was assessed by the Launey Slade Hallucination Scale (LSHS) in 25 healthy individuals who varied in their propensity to hear voices. Brain volume and microstructure of the STG was assessed by magnetic resonance imaging (MRI). Microstructure was examined by conventional diffusion-tensor imaging as well as by neurite orientation dispersion and density imaging (NODDI). The latter decomposes diffusion-based MRI into multiple compartments that characterize the brain microstructure by its neurite complexity known as orientation dispersion (ODI) and by its neurite density (NDI). Hallucination proneness was negatively correlated with the volume and microstructure (fractional anisotropy, neurite complexity) of the left but not the right STG. The strongest relationship (r = −0.563) was observed for neurite complexity (ODI). No correlation was observed for neurite density (NDI). These findings suggest that there is a relationship between the volume and the microstructure of the left STG and hallucination proneness. Dendritic complexity (but not neurite density) is inversely related to hallucination proneness. Metrics based on multi-compartment diffusion models seem to be more sensitive for hallucination-related neural processes than conventional MRI-based metrics., Highlights • Hallucination proneness is predicted by structural characteristics of left STG • Hallucination proneness negatively correlates with left STG volume • Hallucination proneness negatively correlates with left STG fractional anisotropy • Hallucination proneness negatively correlates with left STG orientation dispersion • Reduced functional integration may be due to reduced dendritic complexity of neurons

Locus of control (LOC) is an important personality trait. LOC over cognitive competency reflects an individual's perceived control of desired cognitive outcomes, which is critical for maintaining successful cognitive aging. It is important to understand the neural substrates of LOC over cognitive competency in older adults, especially for individuals at high risk of dementia. Here, we characterized a cohesive functional and structural connectivity profile underlying LOC among 55 older adults with amnestic mild cognitive impairment (aMCI), combining resting-state functional magnetic resonance imaging and diffusion tensor imaging. The results showed that both functional and structural connectivity between the medial prefrontal cortex and amygdala were significantly correlated with external LOC. The functional connectivity mediated the correlation between structural connectivity and external LOC. In addition, aging-associated neurodegeneration moderated the relationship between structural connectivity and external LOC, showing that the structural connectivity was positively correlated with external LOC in low, but not high neurodegeneration. Our results suggest a critical role of the functional amygdala-frontal network, which may serve as a bridge between its white matter tract and LOC over cognitive competency in groups at high risk for dementia., Highlights • Amygdala connectivity is associated with external locus of control (eLOC). • Functional connectivity mediates the relationship of structural connectivity and eLOC. • Neurodegeneration disrupts the relationship between structural connectivity and eLOC.

Introduction Mutations in the progranulin (GRN) gene are a major source of inherited frontotemporal degeneration (FTD) spectrum disorders associated with TDP-43 proteinopathy. We use structural MRI to identify regions of baseline differences and longitudinal changes in gray matter (GM) and white matter (WM) in presymptomatic GRN mutation carriers (pGRN+) compared to young controls (yCTL). Methods Cognitively intact first-degree relatives of symptomatic GRN+ FTD patients with identified GRN mutations (pGRN+; N = 11, mean age = 41.4) and matched yCTL (N = 11, mean age = 53.6) were identified. They completed a MRI session with T1-weighted imaging to assess GM density (GMD) and diffusion-weighted imaging (DWI) to assess fractional anisotropy (FA). Participants completed a follow-up session with T1 and DWI imaging (pGRN+ mean interval 2.20 years; yCTL mean interval 3.27 years). Annualized changes of GMD and FA were also compared. Results Relative to yCTL, pGRN+ individuals displayed reduced GMD at baseline in bilateral orbitofrontal, insular, and anterior temporal cortices. pGRN+ also showed greater annualized GMD changes than yCTL at follow-up in right orbitofrontal and left occipital cortices. We also observed reduced FA at baseline in bilateral superior longitudinal fasciculus, left corticospinal tract, and frontal corpus callosum in pGRN+ relative to yCTL, and pGRN+ displayed greater annualized longitudinal FA change in right superior longitudinal fasciculus and frontal corpus callosum. Conclusions Longitudinal MRI provides evidence of progressive GM and WM changes in pGRN+ participants relative to yCTL. Structural MRI illustrates the natural history of presymptomatic GRN carriers, and may provide an endpoint during disease-modifying treatment trials for pGRN+ individuals at risk for FTD., Highlights • Presymptomatic GRN mutation carriers (pGRN+) show decreased gray matter and white matter relative to young controls (yCTL) • pGRN+ show greater longitudinal changes in gray matter and white matter relative to yCTL • Regions with decreased gray matter and white matter in pGRN+ are in regions showing disease in symptomatic GRN+

We perform a review of the literature in the field of white matter tractography for neurosurgical planning, focusing on those works where tractography was correlated with clinical information such as patient outcome, clinical functional testing, or electro-cortical stimulation. We organize the review by anatomical location in the brain and by surgical procedure, including both supratentorial and infratentorial pathologies, and excluding spinal cord applications. Where possible, we discuss implications of tractography for clinical care, as well as clinically relevant technical considerations regarding the tractography methods. We find that tractography is a valuable tool in variable situations in modern neurosurgery. Our survey of recent reports demonstrates multiple potentially successful applications of white matter tractography in neurosurgery, with progress towards overcoming clinical challenges of standardization and interpretation., Highlights • We review state-of-the-art white matter tractography for surgical planning. • Review is organized by anatomical location in the brain and by surgical procedure. • Clinically relevant technical considerations are provided. • Tractography is a valuable tool in variable situations in modern neurosurgery.

The symptoms of idiopathic normal pressure hydrocephalus (iNPH) can be improved by shunt surgery, but prediction of treatment outcome is not established. We investigated changes of the corticospinal tract (CST) in iNPH before and after shunt surgery by using diffusion microstructural imaging, which infers more specific tissue properties than conventional diffusion tensor imaging. Two biophysical models were used: neurite orientation dispersion and density imaging (NODDI) and white matter tract integrity (WMTI). In both methods, the orientational coherence within the CSTs was higher in patients than in controls, and some normalization occurred after the surgery in patients, indicating axon stretching and recovery. The estimated axon density was lower in patients than in controls but remained unchanged after the surgery, suggesting its potential as a marker for irreversible neuronal damage. In a Monte-Carlo simulation that represented model axons as undulating cylinders, both NODDI and WMTI separated the effects of axon density and undulation. Thus, diffusion MRI may distinguish between reversible and irreversible microstructural changes in iNPH. Our findings constitute a step towards a quantitative image biomarker that reflects pathological process and treatment outcomes of iNPH., Highlights • NODDI and WMTI provide markers of reversible and irreversible changes in iNPH. • Measures of axon orientation indicated recovery from stretching after surgery. • Axon density remained low after surgery, suggesting chronic neuronal damage. • Axon stretching in simulations differentially affected diffusion metrics.

Highlights • Diffusion MRI measures provide insight into gray matter microstructure in PTSD. • Amygdala-hippocampal and cingulate microstructure is associated with PTSD severity. • Mild TBI may exacerbate the impact of limbic microstructure on PTSD severity. • Neural contributors to psychiatric disorder severity may be affected by brain injury., Background Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals, yet the neuropathological mechanisms that contribute to this disorder remain to be fully determined. Moreover, it is unclear how exposure to mild traumatic brain injury (mTBI), a condition that is often comorbid with PTSD, particularly among military personnel, affects the clinical and neurological presentation of PTSD. To address these issues, the present study explores relationships between PTSD symptom severity and the microstructure of limbic and paralimbic gray matter brain regions, as well as the impact of mTBI comorbidity on these relationships. Methods Structural and diffusion MRI data were acquired from 102 male veterans who were diagnosed with current PTSD. Diffusion data were analyzed with free-water imaging to quantify average CSF-corrected fractional anisotropy (FA) and mean diffusivity (MD) in 18 limbic and paralimbic gray matter regions. Associations between PTSD symptom severity and regional average dMRI measures were examined with repeated measures linear mixed models. Associations were studied separately in veterans with PTSD only, and in veterans with PTSD and a history of military mTBI. Results Analyses revealed that in the PTSD only cohort, more severe symptoms were associated with higher FA in the right amygdala-hippocampus complex, lower FA in the right cingulate cortex, and lower MD in the left medial orbitofrontal cortex. In the PTSD and mTBI cohort, more severe PTSD symptoms were associated with higher FA bilaterally in the amygdala-hippocampus complex, with higher FA bilaterally in the nucleus accumbens, with lower FA bilaterally in the cingulate cortex, and with higher MD in the right amygdala-hippocampus complex. Conclusions These findings suggest that the microstructure of limbic and paralimbic brain regions may influence PTSD symptomatology. Further, given the additional associations observed between microstructure and symptom severity in veterans with head trauma, we speculate that mTBI may exacerbate the impact of brain microstructure on PTSD symptoms, especially within regions of the brain known to be vulnerable to chronic stress. A heightened sensitivity to the microstructural environment of the brain could partially explain why individuals with PTSD and mTBI comorbidity experience more severe symptoms and poorer illness prognoses than those without a history of brain injury. The relevance of these microstructural findings to the conceptualization of PTSD as being a disorder of stress-induced neuronal connectivity loss is discussed.

Highlights • Aerobic fitness level, but not physical activity, is related to white matter properties in the brain. • The relation between physical activity and working memory is moderated by fractional anisotropy (FA) of the corpus callosum. • The FA of the corpus callosum and superior corona radiata moderates the relation between aerobic fitness and working memory., Physical activity and exercise beneficially link to brain properties and cognitive functions in older adults, but the findings concerning adolescents remain tentative. During adolescence, the brain undergoes significant changes, which are especially pronounced in white matter. Studies provide contradictory evidence regarding the influence of physical activity or aerobic-exercise on executive functions in youth. Little is also known about the link between both fitness and physical activity with the brain’s white matter during puberty. We investigated the connection between aerobic fitness and physical activity with the white matter in 59 adolescents. We further determined whether white matter interacts with the connection of fitness or physical activity with core executive functions. Our results show that only the level of aerobic fitness, but not of physical activity relates to white matter. Furthermore, the white matter of the corpus callosum and the right superior corona radiata moderates the links of aerobic fitness and physical activity with working memory. Our results suggest that aerobic fitness and physical activity have an unequal contribution to the white matter properties in adolescents. We propose that the differences in white matter properties could underlie the variations in the relationship between either physical activity or aerobic fitness with working memory.

Highlights • Patients with congenital heart disease (CHD) are at risk for lower working memory. • CHD patients showed widespread alterations in white matter microstructure using DTI. • Alterations in frontal white matter were associated with working memory problems. • This association was independent of CHD type, IQ and group., Children and adolescents with congenital heart disease (CHD) are at risk for mild to moderate cognitive impairments. In particular, impaired working memory performance has been found in CHD patients of all ages. Working memory is an important domain of higher order cognitive function and is crucial for everyday activities, with emerging importance in adolescence. However, the underlying neural correlate of working memory impairments in CHD is not yet fully understood. Diffusion tensor imaging and tract based spatial statistics analyses were conducted in 47 adolescent survivors of childhood cardiopulmonary bypass surgery (24 females) and in 44 healthy controls (24 females) between 11 and 16 years of age (mean age = 13.9, SD = 1.6). Fractional anisotropy (FA) of white matter diffusion was compared between groups and was correlated with working memory performance, derived from the Wechsler Intelligence Scale for Children-IV. CHD patients had significantly poorer working memory compared to controls (p = 0.001). Widespread bilateral reduction in FA was observed in CHD patients compared to healthy controls (threshold-free cluster enhancement (TFCE) corrected p < 0.05). This reduction in FA was present both in cyanotic and acyanotic CHD patients compared to healthy controls (both p < 0.001). The FA reduction in the frontal lobe, mainly in the forceps minor, was associated with poorer working memory performance in both patients with CHD and healthy controls (TFCE corrected p < 0.05). The current findings underline that in CHD patients, irrespective of disease severity, disrupted or delayed maturation of white matter may persist into adolescence and is associated with working memory impairments, particularly if present in the frontal lobe. Adolescence, which is a crucial period for prefrontal brain maturation, may offer a window of opportunity for intervention in order to support the maturation of frontal brain regions and therefore improve higher order cognitive function in patients with CHD.