Mind and skin: Exploring the links between inflammation, sleep disturbance and neurocognitive function in patients with atopic dermatitis.

Atopic dermatitis (AD) is a chronic, pruritic and inflammatory, dry skin condition with many known comorbidities. These include airway disease, food allergies, atopic eye disease and autoimmune conditions. Furthermore, there is often significant sleep disturbance as well as increased psychological distress and mental health problems. Severe AD therefore often has a significant impact on the quality of life of both patients and their families. In this review we discuss recent findings on the putative links between AD, its association with itch, sleep disturbance and neuropsychiatric morbidity, including the role of inflammation in these conditions. Itch was thought to predominantly drive sleep disruption in AD. We now understand changes in sleep influence immune cell distribution and the associated inflammatory cytokines, which suggests a bidirectional relationship between AD and sleep. We also increasingly recognize inflammation as a key driver in psychological symptoms and disorders. The link between cutaneous, systemic and possible brain inflammation could at least in part be driven by the sleep deprivation and itch-driven neuronal proliferation seen in AD.

Widespread, depth-dependent cortical microstructure alterations in pediatric focal epilepsy.

OBJECTIVE: Tissue abnormalities in focal epilepsy may extend beyond the presumed focus. The underlying pathophysiology of these broader changes is unclear, and it is not known whether they result from ongoing disease processes or treatment-related side effects, or whether they emerge earlier. Few studies have focused on the period of onset for most focal epilepsies, childhood. Fewer still have utilized quantitative magnetic resonance imaging (MRI), which may provide a more sensitive and interpretable measure of tissue microstructural change. Here, we aimed to determine common spatial modes of changes in cortical architecture in children with heterogeneous drug-resistant focal epilepsy and, secondarily, whether changes were related to disease severity. METHODS: To assess cortical microstructure, quantitative T1 and T2 relaxometry (qT1 and qT2) was measured in 43 children with drug-resistant focal epilepsy (age range = 4-18 years) and 46 typically developing children (age range = 2-18 years). We assessed depth-dependent qT1 and qT2 values across the neocortex, as well as their gradient of change across cortical depths. We also determined whether global changes seen in group analyses were driven by focal pathologies in individual patients. Finally, as a proof-of-concept, we trained a classifier using qT1 and qT2 gradient maps from patients with radiologically defined abnormalities (MRI positive) and healthy controls, and tested whether this could classify patients without reported radiological abnormalities (MRI negative). RESULTS: We uncovered depth-dependent qT1 and qT2 increases in widespread cortical areas in patients, likely representing microstructural alterations in myelin or gliosis. Changes did not correlate with disease severity measures, suggesting they may represent antecedent neurobiological alterations. Using a classifier trained with MRI-positive patients and controls, sensitivity was 71.4% at 89.4% specificity on held-out MRI-negative patients. SIGNIFICANCE: These findings suggest the presence of a potential imaging endophenotype of focal epilepsy, detectable irrespective of radiologically identified abnormalities.

Tissue optimization strategies for high-quality ex vivo diffusion imaging.

Ex vivo diffusion imaging can be used to study healthy and pathological tissue microstructure in the rodent brain with high resolution, providing a link between in vivo MRI and ex vivo microscopy techniques. Major challenges for the successful acquisition of ex vivo diffusion imaging data however are changes in the relaxivity and diffusivity of brain tissue following perfusion fixation. In this study we address this question by examining the combined effects of tissue preparation factors that influence signal-to-noise ratio (SNR) and consequently image quality, including fixative concentration, contrast agent concentration and tissue rehydration time. We present an optimization strategy combining these factors to manipulate the T 1 and T 2 of fixed tissue and maximize SNR efficiency. We apply this strategy in the rat brain, for a diffusion-weighted spin echo protocol with TE = 27 ms on a 9.4 T scanner with a 39 mm volume coil and 660 mT/m 114 mm gradient insert. We used a reduced fixative concentration of 2% paraformaldehyde (PFA), rehydration time more than 20 days, 15 mM Gd-DTPA in perfusate and TR 250 ms. This resulted in a doubling of SNR and an increase in SNR per unit time of 135% in cortical grey matter and 88% in white matter compared with 4% PFA and no contrast agent. This improved SNR efficiency enabled the acquisition of excellent-quality high-resolution (78 µ m isotropic voxel size) diffusion data with b = 4000 s/mm 2 , 30 diffusion directions and a field of view of 40 × 13 × 18 mm3 in less than 4 days. It was also possible to achieve comparable data quality for a standard resolution (150 µ m) diffusion dataset in 2 1 4 h. In conclusion, the tissue optimization strategy presented here may be used to improve SNR, increase spatial resolution and/or allow faster acquisitions in preclinical ex vivo diffusion MRI experiments.

Motion corrected silent ZTE neuroimaging.

PURPOSE: To develop self-navigated motion correction for 3D silent zero echo time (ZTE) based neuroimaging and characterize its performance for different types of head motion. METHODS: The proposed method termed MERLIN (Motion Estimation & Retrospective correction Leveraging Interleaved Navigators) achieves self-navigation by using interleaved 3D phyllotaxis k-space sampling. Low resolution navigator images are reconstructed continuously throughout the ZTE acquisition using a sliding window and co-registered in image space relative to a fixed reference position. Rigid body motion corrections are then applied retrospectively to the k-space trajectory and raw data and reconstructed into a final, high-resolution ZTE image. RESULTS: MERLIN demonstrated successful and consistent motion correction for magnetization prepared ZTE images for a range of different instructed motion paradigms. The acoustic noise response of the self-navigated phyllotaxis trajectory was found to be only slightly above ambient noise levels (<4 dBA). CONCLUSION: Silent ZTE imaging combined with MERLIN addresses two major challenges intrinsic to MRI (i.e., subject motion and acoustic noise) in a synergistic and integrated manner without increase in scan time and thereby forms a versatile and powerful framework for clinical and research MR neuroimaging applications.

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions.

PURPOSE: Validation of quantitative MR measures for myelin imaging in the postmortem multiple sclerosis spinal cord. METHODS: Four fixed spinal cord samples were imaged first with a 3T clinical MR scanner to identify areas of interest for scanning, and then with a 7T small bore scanner using a multicomponent-driven equilibrium single-pulse observation of T1 and T2 protocol to produce apparent proton density, T1 , T2 , myelin water, intracellular water, and free-water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. RESULTS: Excellent correspondence was found between high-resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. CONCLUSION: High-resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord.

Systemic α-synuclein injection triggers selective neuronal pathology as seen in patients with Parkinson's disease.

Parkinson's disease (PD) is an α-synucleinopathy characterized by the progressive loss of specific neuronal populations. Here, we develop a novel approach to transvascularly deliver proteins of complex quaternary structures, including α-synuclein preformed fibrils (pff). We show that a single systemic administration of α-synuclein pff triggers pathological transformation of endogenous α-synuclein in non-transgenic rats, which leads to neurodegeneration in discrete brain regions. Specifically, pff-exposed animals displayed a progressive deterioration in gastrointestinal and olfactory functions, which corresponded with the presence of cellular pathology in the central and enteric nervous systems. The α-synuclein pathology generated was both time dependent and region specific. Interestingly, the most significant neuropathological changes were observed in those brain regions affected in the early stages of PD. Our data therefore demonstrate for the first time that a single, transvascular administration of α-synuclein pff can lead to selective regional neuropathology resembling the premotor stage of idiopathic PD. Furthermore, this novel delivery approach could also be used to deliver a range of other pathogenic, as well as therapeutic, protein cargos transvascularly to the brain.

Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks.

Inflammation is associated with depressive symptoms and innate immune mechanisms are likely causal in some cases of major depression. Systemic inflammation also perturbs brain function and microstructure, though how these are related remains unclear. We recruited N = 46 healthy controls, and N = 83 depressed cases stratified by CRP (> 3 mg/L: N = 33; < 3 mg/L: N = 50). All completed clinical assessment, venous blood sampling for C-reactive protein (CRP) assay, and brain magnetic resonance imaging (MRI). Micro-structural MRI parameters including proton density (PD), a measure of tissue water content, were measured at 360 cortical and 16 subcortical regions. Resting-state fMRI time series were correlated to estimate functional connectivity between individual regions, as well as the sum of connectivity (weighted degree) of each region. Multiple tests for regional analysis were controlled by the false discovery rate (FDR = 5%). We found that CRP was significantly associated with PD in precuneus, posterior cingulate cortex (pC/pCC) and medial prefrontal cortex (mPFC); and with functional connectivity between pC/pCC, mPFC and hippocampus. Depression was associated with reduced weighted degree of pC/pCC, mPFC, and other nodes of the default mode network (DMN). Thus CRP-related increases in proton density-a plausible marker of extracellular oedema-and changes in functional connectivity were anatomically co-localised with DMN nodes that also demonstrated significantly reduced hubness in depression. We suggest that effects of peripheral inflammation on DMN node micro-structure and connectivity may mediate inflammatory effects on depression.

3D APT and NOE CEST-MRI of healthy volunteers and patients with non-enhancing glioma at 3 T.

OBJECTIVE: Clinical application of chemical exchange saturation transfer (CEST) can be performed with investigation of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects. Here, we investigated APT- and NOE-weighted imaging based on advanced CEST metrics to map tumor heterogeneity of non-enhancing glioma at 3 T. MATERIALS AND METHODS: APT- and NOE-weighted maps based on Lorentzian difference (LD) and inverse magnetization transfer ratio (MTRREX) were acquired with a 3D snapshot CEST acquisition at 3 T. Saturation power was investigated first by varying B1 (0.5-2 µT) in 5 healthy volunteers then by applying B1 of 0.5 and 1.5 µT in 10 patients with non-enhancing glioma. Tissue contrast (TC) and contrast-to-noise ratios (CNR) were calculated between glioma and normal appearing white matter (NAWM) and grey matter, in APT- and NOE-weighted images. Volume percentages of the tumor showing hypo/hyperintensity (VPhypo/hyper,CEST) in APT/NOE-weighted images were calculated for each patient. RESULTS: LD APT resulting from using a B1 of 1.5 µT was found to provide significant positive TCtumor,NAWM and MTRREX NOE (B1 of 1.5 µT) provided significant negative TCtumor,NAWM in tissue differentiation. MTRREX-based NOE imaging under 1.5 µT provided significantly larger VPhypo,CEST than MTRREX APT under 1.5 µT. CONCLUSION: This work showed that with a rapid CEST acquisition using a B1 saturation power of 1.5 µT and covering the whole tumor, analysis of both LD APT and MTRREX NOE allows for observing tumor heterogeneity, which will be beneficial in future studies using CEST-MRI to improve imaging diagnostics for non-enhancing glioma.

Mapping tumour heterogeneity with pulsed 3D CEST MRI in non-enhancing glioma at 3 T.

OBJECTIVE: Amide proton transfer (APT) weighted chemical exchange saturation transfer (CEST) imaging is increasingly used to investigate high-grade, enhancing brain tumours. Non-enhancing glioma is currently less studied, but shows heterogeneous pathophysiology with subtypes having equally poor prognosis as enhancing glioma. Here, we investigate the use of CEST MRI to best differentiate non-enhancing glioma from healthy tissue and image tumour heterogeneity. MATERIALS & METHODS: A 3D pulsed CEST sequence was applied at 3 Tesla with whole tumour coverage and 31 off-resonance frequencies (+6 to -6 ppm) in 18 patients with non-enhancing glioma. Magnetisation transfer ratio asymmetry (MTRasym) and Lorentzian difference (LD) maps at 3.5 ppm were compared for differentiation of tumour versus normal appearing white matter. Heterogeneity was mapped by calculating volume percentages of the tumour showing hyperintense APT-weighted signal. RESULTS: LDamide gave greater effect sizes than MTRasym to differentiate non-enhancing glioma from normal appearing white matter. On average, 17.9 % ± 13.3 % (min-max: 2.4 %-54.5 %) of the tumour volume showed hyperintense LDamide in non-enhancing glioma. CONCLUSION: This works illustrates the need for whole tumour coverage to investigate heterogeneity in increased APT-weighted CEST signal in non-enhancing glioma. Future work should investigate whether targeting hyperintense LDamide regions for biopsies improves diagnosis of non-enhancing glioma.

Detection of covert lesions in focal epilepsy using computational analysis of multimodal magnetic resonance imaging data.

OBJECTIVE: To compare the location of suspect lesions detected by computational analysis of multimodal magnetic resonance imaging data with areas of seizure onset, early propagation, and interictal epileptiform discharges (IEDs) identified with stereoelectroencephalography (SEEG) in a cohort of patients with medically refractory focal epilepsy and radiologically normal magnetic resonance imaging (MRI) scans. METHODS: We developed a method of lesion detection using computational analysis of multimodal MRI data in a cohort of 62 control subjects, and 42 patients with focal epilepsy and MRI-visible lesions. We then applied it to detect covert lesions in 27 focal epilepsy patients with radiologically normal MRI scans, comparing our findings with the areas of seizure onset, early propagation, and IEDs identified at SEEG. RESULTS: Seizure-onset zones (SoZs) were identified at SEEG in 18 of the 27 patients (67%) with radiologically normal MRI scans. In 11 of these 18 cases (61%), concordant abnormalities were detected by our method. In the remaining seven cases, either early seizure propagation or IEDs were observed within the abnormalities detected, or there were additional areas of imaging abnormalities found by our method that were not sampled at SEEG. In one of the nine patients (11%) in whom SEEG was inconclusive, an abnormality, which may have been involved in seizures, was identified by our method and was not sampled at SEEG. SIGNIFICANCE: Computational analysis of multimodal MRI data revealed covert abnormalities in the majority of patients with refractory focal epilepsy and radiologically normal MRI that co-located with SEEG defined zones of seizure onset. The method could help identify areas that should be targeted with SEEG when considering epilepsy surgery.

Magnetization transfer and frequency distribution effects in the SSFP ellipse.

PURPOSE: To demonstrate that quantitative magnetization transfer (qMT) parameters can be extracted from steady-state free-precession (SSFP) data with no external T1 map or banding artifacts. METHODS: SSFP images with multiple MT weightings were acquired and qMT parameters fitted with a two-stage elliptical signal model. RESULTS: Monte Carlo simulations and data from a 3T scanner indicated that most qMT parameters could be recovered with reasonable accuracy. Systematic deviations from theory were observed in white matter, consistent with previous literature on frequency distribution effects. CONCLUSIONS: qMT parameters can be extracted from SSFP data alone, in a manner robust to banding artifacts, despite several confounds.

Steady-state imaging with inhomogeneous magnetization transfer contrast using multiband radiofrequency pulses.

PURPOSE: Inhomogeneous magnetization transfer (ihMT) is an emerging form of MRI contrast that may offer high specificity for myelinated tissue. Existing ihMT and pulsed MT sequences often use separate radiofrequency pulses for saturation and signal excitation. This study investigates the use of nonselective multiband radiofrequency pulses for simultaneous off-resonance saturation and on-resonance excitation specifically for generation of ihMT contrast within rapid steady-state pulse sequences. THEORY AND METHODS: A matrix-based signal modeling approach was developed and applied for both balanced steady state free precession and spoiled gradient echo sequences, accounting specifically for multiband pulses. Phantom experiments were performed using a combination of balanced steady state free precession and spoiled gradient echo sequences, and compared with model fits. A human brain imaging exam was performed using balanced steady state free precession sequences to demonstrate the achieved contrast. RESULTS: A simple signal model derived assuming instantaneous radiofrequency pulses was shown to agree well with full integration of the governing equations and provided fits to phantom data for materials with strong ihMT contrast (PL161 root mean square error = 0.9%, and hair conditioner root mean square error = 2.4%). In vivo ihMT ratio images showed the expected white matter contrast that has been seen by other ihMT investigations, and the observed ihMT ratios corresponded well with predictions. CONCLUSIONS: ihMT contrast can be generated by integrating multiband radiofrequency pulses directly into both spoiled gradient echo and balanced steady state free precession sequences, and the presented signal modeling approach can be used to understand the acquired signals.

Controlled saturation magnetization transfer for reproducible multivendor variable flip angle T1 and T2 mapping.

PURPOSE: The widespread clinical application of quantitative MRI has been hindered by a lack of reproducibility across sites and vendors. Previous work has attributed this to incorrect B1 mapping or insufficient spoiling conditions. We recently proposed the controlled saturation magnetization transfer (CSMT) framework and hypothesized that the lack of reproducibility can also be attributed to magnetization transfer effects. This work seeks to validate this hypothesis and demonstrate that reproducible multivendor single-pool relaxometry can be achieved with the CSMT approach. METHODS: Three healthy volunteers were scanned on scanners from 3 vendors (GE Healthcare, Philips, Siemens). An extensive set of images necessary for joint T1 and T2 estimation were acquired with (1) each vendor default RF pulses and spoiling conditions; (2) harmonized RF spoiling; and (3) harmonized RF spoiling and CSMT pulses. Different subsets of images were used to generate 6 different T1 and T2 maps for each subject's data from each vendor. Cross-protocol, cross-vendor, and test/retest variability were estimated. RESULTS: Harmonized RF spoiling conditions are insufficient to ensure good cross-vendor reproducibility. Controlled saturation magnetization transfer allows cross-protocol variability to be reduced from 18.3% to 4.0%. Whole-brain variability using the same protocol was reduced from a maximum of 19% to 4.5% across sites. Both CSMT and native vendor RF conditions have a reported variability of less than 5% for repeat measures on the same vendor. CONCLUSION: Magnetization transfer effects are a major contributor to intersite/intrasite variability of T1 and T2 estimation. Controlled saturation magnetization transfer stabilizes these effects, paving the way for the use of single-pool T1 and T2 as a reliable source for clinical diagnosis across sites.

Inherent and unpredictable bias in multi-component DESPOT myelin water fraction estimation.

Multicomponent driven equilibrium steady-state observation of T1 and T2 (mcDESPOT) aims to quantify the Myelin Water Fraction (MWF) using a two-pool microstructural model. The MWF has been used to track neurodevelopment and neurodegeneration and has been histologically correlated to myelin content. mcDESPOT has a clinically feasible acquisition time and high signal-to-noise ratio (SNR) relative to other MWF techniques. However, disagreement exists in the literature between experimental studies that show MWF maps with plausible grey matter-white matter (GM-WM) contrast and theoretical work that questions the accuracy and precision of mcDESPOT. We demonstrate that mcDESPOT parameter estimation is inaccurate and imprecise if intercompartmental exchange is included in the microstructural model, but that significant bias results if exchange is neglected. The source of apparent MWF contrast is likely due to the complex convergence behaviour of the Stochastic Region Contraction (SRC) method commonly used to fit the mcDESPOT model. mcDESPOT-derived parameter estimates are hence not directly relatable to the underlying microstructural model and are only comparable to others using similar acquisition schemes and fitting constraints.

Alterations in brain microstructure in rats that develop abnormal aggression following peripubertal stress.

Exposure to early adversity is implicated in the development of aggressive behaviour later in life in some but not all individuals. The reasons for the variability in response to such experiences are not clear but may relate to pre-existing individual differences that influence their downstream effects. Applying structural magnetic resonance imaging (MRI) to a rat model of abnormal aggression induced by peripubertal stress, we examined whether individual differences in the development of an aggressive phenotype following stress exposure were underpinned by variation in the structure of aggression-associated, corticolimbic brain regions. We also assessed whether responsiveness of the hypothalamic-pituitary-adrenal axis to stress was associated with neurobehavioural outcome following adversity. A subset of the rats exposed to peripubertal stress developed an aggressive phenotype, while the remaining rats were affected in other behavioural domains, such as increased anxiety-like behaviours and reduced sociability. Peripubertal stress led to changes in tissue microstructure within prefrontal cortex, amygdala and hippocampal formation only in those individuals displaying an aggressive phenotype. Attenuated glucocorticoid response to stress during juvenility predicted the subsequent development of an aggressive phenotype in peripubertal stress-exposed rats. Our study establishes a link between peripubertal stress exposure in rats and structural deviations in brain regions linked to abnormal aggression and points towards low glucocorticoid responsiveness to stress as a potential underlying mechanism. We additionally highlight the importance of considering individual differences in behavioural response to stress when determining neurobiological correlates.

An investigation of regional cerebral blood flow and tissue structure changes after acute administration of antipsychotics in healthy male volunteers.

Chronic administration of antipsychotic drugs has been linked to structural brain changes observed in patients with schizophrenia. Recent MRI studies have shown rapid changes in regional brain volume following just a single dose of these drugs. However, it is not clear if these changes represent real volume changes or are artefacts ("apparent" volume changes) due to drug-induced physiological changes, such as increased cerebral blood flow (CBF). To address this, we examined the effects of a single, clinical dose of three commonly prescribed antipsychotics on quantitative measures of T1 and regional blood flow of the healthy human brain. Males (n = 42) were randomly assigned to one of two parallel groups in a double-blind, placebo-controlled, randomized, three-period cross-over study design. One group received a single oral dose of either 0.5 or 2 mg of risperidone or placebo during each visit. The other received olanzapine (7.5 mg), haloperidol (3 mg), or placebo. MR measures of quantitative T1, CBF, and T1-weighted images were acquired at the estimated peak plasma concentration of the drug. All three drugs caused localized increases in striatal blood flow, although drug and region specific effects were also apparent. In contrast, all assessments of T1 and brain volume remained stable across sessions, even in those areas experiencing large changes in CBF. This illustrates that a single clinically relevant oral dose of an antipsychotic has no detectable acute effect on T1 in healthy volunteers. We further provide a methodology for applying quantitative imaging methods to assess the acute effects of other compounds on structural MRI metrics. Hum Brain Mapp 39:319-331, 2018. © 2017 Wiley Periodicals, Inc.

Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders.

Prenatal exposure to maternal infection increases the risk of neurodevelopmental disorders, including schizophrenia and autism. The molecular processes underlying this pathological association, however, are only partially understood. Here, we combined unbiased genome-wide transcriptional profiling with follow-up epigenetic analyses and structural magnetic resonance imaging to explore convergent molecular and neuromorphological alterations in corticostriatal areas of adult offspring exposed to prenatal immune activation. Genome-wide transcriptional profiling revealed that prenatal immune activation caused a differential expression of 116 and 251 genes in the medial prefrontal cortex and nucleus accumbens, respectively. A large part of genes that were commonly affected in both brain areas were related to myelin functionality and stability. Subsequent epigenetic analyses indicated that altered DNA methylation of promoter regions might contribute to the differential expression of myelin-related genes. Quantitative relaxometry comparing T1, T2, and myelin water fraction revealed sparse increases in T1 relaxation times and consistent reductions in T2 relaxation times. Together, our multi-system approach demonstrates that prenatal viral-like immune activation causes myelin-related transcriptional and epigenetic changes in corticostriatal areas. Even though these abnormalities do not seem to be associated with overt white matter reduction, they may provide a molecular mechanism whereby prenatal infection can impair myelin functionality and stability.

Delayed intramuscular human neurotrophin-3 improves recovery in adult and elderly rats after stroke.

There is an urgent need for a therapy that reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. We show here that intramuscular delivery of neurotrophin-3 (NT3, encoded by NTF3) can induce sensorimotor recovery when treatment is initiated 24 h after stroke. Specifically, in two randomized, blinded preclinical trials, we show improved sensory and locomotor function in adult (6 months) and elderly (18 months) rats treated 24 h following cortical ischaemic stroke with human NT3 delivered using a clinically approved serotype of adeno-associated viral vector (AAV1). Importantly, AAV1-hNT3 was given in a clinically-feasible timeframe using a straightforward, targeted route (injections into disabled forelimb muscles). Magnetic resonance imaging and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, treatment caused corticospinal axons from the less affected hemisphere to sprout in the spinal cord. This treatment is the first gene therapy that reverses disability after stroke when administered intramuscularly in an elderly body. Importantly, phase I and II clinical trials by others show that repeated, peripherally administered high doses of recombinant NT3 are safe and well tolerated in humans with other conditions. This paves the way for NT3 as a therapy for stroke.