Association of Cumulative Lifetime Exposure to Female Hormones With Cerebral Small Vessel Disease in Postmenopausal Women in the UK Biobank.

BACKGROUND AND OBJECTIVES: Rates of cerebrovascular disease increase after menopause, which is often attributed to the absence of hormones. It remains unknown whether the cumulative exposure to hormones across a female person's premenopausal life extends the window of cerebrovascular protection to the postmenopausal period. To investigate this, we examined the relationship between lifetime hormone exposure (LHE) and cerebral small vessel disease in more than 9,000 postmenopausal women in the UK-Biobank. METHODS: The cohort consisted of women (aged 40-69 years) who attended one of 22 research centers across the United Kingdom between 2006 and 2010. Women were excluded if they were premenopausal when scanned, had missing reproductive history data, self-reported neurologic disorders, brain cancer, cerebral vascular incidents, head or neurologic injury, and nervous system infection. Endogenous LHE (LHEEndo) was estimated by summing the number of years pregnant (LHEParity) with the duration of the reproductive period (LHECycle = age menopause - age menarche). Exogenous LHE (LHEExo) was estimated by summing the number of years on oral contraceptives and hormone replacement therapy. Cerebral small vessel disease was determined by estimating white matter hyperintensity volume (WMHV) from T2-fluid-attenuated inversion recovery brain MRI (acquired between 2014 and 2021), normalized to intracranial volume and log-transformed. Multiple linear regressions were used to assess the relationship between LHEEndo on WMHV adjusted for age, cardiovascular risk factors, sociodemographics, and LHEExo. RESULTS: A total of 9,163 postmenopausal women (age 64.21 ± 6.81 years) were retained for analysis. Average LHEEndo was 39.77 ± 3.59 years. Women with higher LHEEndo showed smaller WMHV (adj-R 2 = 0.307, LHEEndo ß = -0.007 [-0.012 to -0.002], p < 0.01). LHEParity and LHECycle were independent contributors to WMHV (adj-R 2 = 0.308, p << 0.001; LHEParity ß = -0.022 [-0.042 to -0.002], p < 0.05; LHECycle ß = -0.006 [-0.011 to -0.001], p < 0.05). LHEExo was not significantly related to WMHV (LHEExo ß = 0.001 [-0.001 to 0.002], p > 0.05). DISCUSSION: Women with more prolonged exposure to endogenous hormones show relatively smaller burden of cerebral small vessel disease independent of the history of oral contraceptive use or hormone replacement therapy. Our results highlight the critical role endogenous hormones play in female brain health and provide real-world evidence of the protective effects premenopausal endogenous hormone exposure plays on postmenopausal cerebrovascular health.

The relationship between persistent organic pollutants and Attention Deficit Hyperactivity Disorder phenotypes: Evidence from task-based neural activity in an observational study of a community sample of Canadian mother-child dyads.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs), widespread in North America, is associated with increased Attention Deficit/Hyperactivity Disorder (ADHD) symptoms and may be a modifiable risk for ADHD phenotypes. However, the effects of moderate exposure to POPs on task-based inhibitory control performance, related brain function, and ADHD-related symptoms remain unknown, limiting our ability to develop interventions targeting the neural impact of common levels of exposure. OBJECTIVES: The goal of this study was to examine the association between prenatal POP exposure and inhibitory control performance, neural correlates of inhibitory control and ADHD-related symptoms. METHODS: Prospective data was gathered in an observational study of Canadian mother-child dyads, with moderate exposure to POPs, including polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), as part of the GESTation and the Environment (GESTE) cohort in Sherbrooke, Quebec, Canada. The sample included 87 eligible children, 46 with maternal plasma samples, functional magnetic resonance imaging (fMRI) data of Simon task performance at 9-11 years, and parental report of clinical symptoms via the Behavioral Assessment System for Children 3 (BASC-3). Simon task performance was probed via drift diffusion modeling, and parameter estimates were related to POP exposure. Simon task-based fMRI data was modeled to examine the difference in incongruent vs congruent trials in regions of interest (ROIs) identified by meta analysis. RESULTS: Of the 46 participants with complete data, 29 were male, and mean age was 10.42 ± 0.55 years. Increased POP exposure was associated with reduced accuracy (e.g. PCB molar sum rate ratio = 0.95; 95% CI [0.90, 0.99]), drift rate (e.g. for PCB molar sum ß = -0.42; 95% CI [-0.77, -0.07]), and task-related brain activity (e.g. in inferior frontal cortex for PCB molar sum ß = -0.35; 95% CI [-0.69, -0.02]), and increased ADHD symptoms (e.g. hyperactivity PCB molar sum ß = 2.35; 95%CI [0.17, 4.53]), supporting the possibility that prenatal exposure to POPs is a modifiable risk for ADHD phenotypes. DISCUSSION: We showed that exposure to POPs is related to task-based changes in neural activity in brain regions important for inhibitory control, suggesting a biological mechanism underlying previously documented associations between POPs and neurobehavioral deficits found in ADHD phenotypes.

The regional effect of serum hormone levels on cerebral blood flow in healthy nonpregnant women.

Sex hormones estrogen (EST) and progesterone (PROG) have received increased attention for their important physiological action outside of reproduction. While studies have shown that EST and PROG have significant impacts on brain function, their impact on the cerebrovascular system in humans remains largely unknown. To address this, we used a multi-modal magnetic resonance imaging (MRI) approach to investigate the link between serum hormones in the follicular phase and luteal phase of the menstrual cycle (MC) with measures of cerebrovascular function (cerebral blood flow [CBF]) and structure (intracranial artery diameter). Fourteen naturally cycling women were recruited and assessed at two-time points of their MC. CBF was derived from pseudo-continuous arterial spin labeling while diameters of the internal carotid and basilar artery was assessed using time of flight magnetic resonance angiography, blood samples were performed after the MRI. Results show that PROG and EST had opposing and spatially distinct effects on CBF: PROG correlated negatively with CBF in anterior brain regions (r = -.86, p < .01), while EST correlations were positive, yet weak and most prominent in posterior areas (r = .78, p < .01). No significant correlations between either hormone or intracranial artery diameter were observed. These results show that EST and PROG have opposing and regionally distinct effects on CBF and that this relationship is likely not due to interactions with large intracranial arteries. Considering that CBF in healthy women appears tightly linked to their current hormonal state, future studies should consider assessing MC-related hormone fluctuations in the design of functional MRI studies in this population.

High-Grade Gliomas Located in the Right Hemisphere Are Associated With Worse Quality of Life.

BACKGROUND: The impact of glioma location on quality of life (QOL) has not been conclusively studied, possibly due to the prohibitively high sample size that standard statistical analyses would require and the inherent heterogeneity of this disease. By using a novel algorithm, we investigated the impact of tumor location on QOL in a limited set of 53 consecutive patients. METHODS: The glial tumors of 53 consecutive patients were segmented and registered to a standardized atlas. The Euclidian distance between 90 brain regions and each tumor's margin was calculated and correlated to the patient's self-reported QOL as measured by the Sherbrooke Neuro-Oncology Assessment Scale questionnaire. RESULTS: QOL was not correlated to tumor volume, though a significant correlation was observed with its proximity to these areas: right supramarginal gyrus, right rolandic operculum, right superior temporal gyrus, right middle temporal gyrus, right angular gyrus, and right inferior parietal lobule. Interestingly, all identified areas are in the right hemisphere, and localized in the temporoparietal region. We postulate that the adverse relation between proximity to these areas and QOL results from disruption in visuospatial functioning. CONCLUSIONS: Although the areas identified in this study are traditionally considered non-eloquent areas, tumor proximity to these regions showed more impact on QOL than any other brain regions. We postulate that this effect is mediated via an adverse impact on the visuospatial functioning.

Diffusion MRI monitoring of specific structures in the irradiated rat brain.

PURPOSE: The analysis of biological and mesoscopic structures properties by diffusion MRI (dMRI) in brain after radiation therapy remains challenging. In our study, we described the consequences associated with an unwanted dose to healthy tissue, assessing radiation-induced brain alterations of living rats with dMRI compared to histopathology and behavioral assays. METHODS: The right primary motor cortex M1 of the rat brain was targeted by stereotactic radiosurgery with a mean radiation dose of 41 Gy. Multidirectional single b-value dMRI data of the whole brain were acquired with a 7T small-animal scanner before irradiation until 110 days post-irradiation. Diffusion tensor imaging metrics, such as fractional anisotropy (FA), mean diffusivity (MD), axial (AD), and radial diffusivity (RD) were compared to brain alterations detected by immunohistochemistry and motor performances measured by a behavioral test. RESULTS: Between days 90 and 110, radiation necrosis was observed into the white matter spreading into M1 . Results showed a reduction of FA in the corpus callosum and in the striatum, which was driven by an increase in RD from 90 to 110 days post-irradiation, whereas only RD increased in M1 . Values of RD and AD increased in the irradiated hippocampus, while FA remained constant. Moreover, an increased MD, AD and RD was observed in the hippocampus that was probably related to inflammation as well as reactive astrogliosis after 110 days post-irradiation. Finally, rats did not exhibit locomotor deficits. CONCLUSIONS: dMRI metrics can assess brain damage; the sensitivity of dMRI metrics depends on the brain region.

Active delineation of Meyer's loop using oriented priors through MAGNEtic tractography (MAGNET).

Streamline tractography algorithms infer connectivity from diffusion MRI (dMRI) by following diffusion directions which are similarly aligned between neighboring voxels. However, not all white matter (WM) fascicles are organized in this manner. For example, Meyer's loop is a highly curved portion of the optic radiation (OR) that exhibits a narrow turn, kissing and crossing pathways, and changes in fascicle dispersion. From a neurosurgical perspective, damage to Meyer's loop carries a potential risk of inducing vision deficits to the patient, especially during temporal lobe resection surgery. To prevent such impairment, achieving an accurate delineation of Meyer's loop with tractography is thus of utmost importance. However, current algorithms tend to under-estimate the full extent of Meyer's loop, mainly attributed to the aforementioned rule for connectivity which requires a direction to be chosen across a field of orientations. In this article, it was demonstrated that MAGNEtic Tractography (MAGNET) can benefit Meyer's loop delineation by incorporating anatomical knowledge of the expected fiber orientation to overcome local ambiguities. A new ROI-mechanism was proposed which supplies additional information to streamline reconstruction algorithms by the means of oriented priors. Their results showed that MAGNET can accurately generate Meyer's loop in all of our 15 child subjects (8 males; mean age 10.2 years ± 3.1). It effectively improved streamline coverage when compared with deterministic tractography, and significantly reduced the distance between the anterior-most portion of Meyer's loop and the temporal pole by 16.7 mm on average, a crucial landmark used for preoperative planning of temporal lobe surgery. Hum Brain Mapp 38:509-527, 2017. © 2016 Wiley Periodicals, Inc.

Understanding the continuum of radionecrosis and vascular disorders in the brain following gamma knife irradiation: An MRI study.

PURPOSE: The radiation dose delivered to brain tumors is limited by the possibility to induce vascular damage and necrosis in surrounding healthy tissue. In the present study, we assessed the ability of MRI to monitor the cascade of events occurring in the healthy rat brain after stereotactic radiosurgery, which could be used to optimize the radiation treatment planning. METHODS: The primary somatosensory forelimb area (S1FL) and the primary motor cortex in the right hemisphere of Fischer rats (n = 6) were irradiated with a single dose of Gamma Knife radiation (Leksell Perfexion, Elekta AG, Stockholm, Sweden). Rats were scanned with a small-animal 7 Tesla MRI scanner before treatment and 16, 21, 54, 82, and 110 days following irradiation. At every imaging session, T2 -weighted (T2 w), Gd-DTPA dynamic contrast-enhanced MRI (DCE-MRI), and T2*-weighted ( T2* w) images were acquired to measure changes in fluid content, blood vessel permeability, and structure, respectively. At days 10, 110, and 140, histopathology was performed on brain sections. Locomotion and spatial memory ability were assessed longitudinally by behavioral tests. RESULTS: No vascular changes were initially observed. After 54 days, a small necrotic volume in the white matter below the S1FL, surrounded by an area presenting significant vascular permeability, was revealed. Between 54 and 110 days, the necrotic volume increased and was accompanied by the formation of a ring-like region, where a mixture of necrosis and permeable blood vessels were observed, as confirmed by histology. Behavioral changes were only observed after day 82. CONCLUSION: Together, DCE-MRI and T2* w images supported by histology provided a coherent picture of the phenomena involved in the formation of new, leaky blood vessels, which was followed by the detection of radionecrosis in a preclinical model of brain irradiation. Magn Reson Med 78:1420-1431, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

3D interactive tractography-informed resting-state fMRI connectivity.

In the past decade, the fusion between diffusion magnetic resonance imaging (dMRI) and functional magnetic resonance imaging (fMRI) has opened the way for exploring structure-function relationships in vivo. As it stands, the common approach usually consists of analysing fMRI and dMRI datasets separately or using one to inform the other, such as using fMRI activation sites to reconstruct dMRI streamlines that interconnect them. Moreover, given the large inter-individual variability of the healthy human brain, it is possible that valuable information is lost when a fixed set of dMRI/fMRI analysis parameters such as threshold values are assumed constant across subjects. By allowing one to modify such parameters while viewing the results in real-time, one can begin to fully explore the sensitivity of structure-function relations and how they differ across brain areas and individuals. This is especially important when interpreting how structure-function relationships are altered in patients with neurological disorders, such as the presence of a tumor. In this study, we present and validate a novel approach to achieve this: First, we present an interactive method to generate and visualize tractography-driven resting-state functional connectivity, which reduces the bias introduced by seed size, shape and position. Next, we demonstrate that structural and functional reconstruction parameters explain a significant portion of intra- and inter-subject variability. Finally, we demonstrate how our proposed approach can be used in a neurosurgical planning context. We believe this approach will promote the exploration of structure-function relationships in a subject-specific aspect and will open new opportunities for connectomics.

Real-time multi-peak tractography for instantaneous connectivity display.

The computerized process of reconstructing white matter tracts from diffusion MRI (dMRI) data is often referred to as tractography. Tractography is nowadays central in structural connectivity since it is the only non-invasive technique to obtain information about brain wiring. Most publicly available tractography techniques and most studies are based on a fixed set of tractography parameters. However, the scale and curvature of fiber bundles can vary from region to region in the brain. Therefore, depending on the area of interest or subject (e.g., healthy control vs. tumor patient), optimal tracking parameters can be dramatically different. As a result, a slight change in tracking parameters may return different connectivity profiles and complicate the interpretation of the results. Having access to tractography parameters can thus be advantageous, as it will help in better isolating those which are sensitive to certain streamline features and potentially converge on optimal settings which are area-specific. In this work, we propose a real-time fiber tracking (RTT) tool which can instantaneously compute and display streamlines. To achieve such real-time performance, we propose a novel evolution equation based on the upsampled principal directions, also called peaks, extracted at each voxel of the dMRI dataset. The technique runs on a single Computer Processing Unit (CPU) without the need for Graphical Unit Processing (GPU) programming. We qualitatively illustrate and quantitatively evaluate our novel multi-peak RTT technique on phantom and human datasets in comparison with the state of the art offline tractography from MRtrix, which is robust to fiber crossings. Finally, we show how our RTT tool facilitates neurosurgical planning and allows one to find fibers that infiltrate tumor areas, otherwise missing when using the standard default tracking parameters.