Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: a critical review for its relevance in acute and long COVID-19.

Current views on immunity support the idea that immunity extends beyond defense functions and is tightly intertwined with several other fields of biology such as virology, microbiology, physiology and ecology. It is also critical for our understanding of autoimmunity and cancer, two topics of great biological relevance and for critical public health considerations such as disease prevention and treatment. Central to this review, the immune system is known to interact intimately with the nervous system and has been recently hypothesized to be involved not only in autonomic and limbic bio-behaviors but also in cognitive function. Herein we review the structural architecture of the brain network involved in immune response. Furthermore, we elaborate upon the implications of inflammatory processes affecting brain-immune interactions as reported recently in pathological conditions due to SARS-Cov-2 virus infection, namely in acute and post-acute COVID-19. Moreover, we discuss how current neuroimaging techniques combined with ad hoc clinical autopsies and histopathological analyses could critically affect the validity of clinical translation in studies of human brain-immune interactions using neuroimaging. Advances in our understanding of brain-immune interactions are expected to translate into novel therapeutic avenues in a vast array of domains including cancer, autoimmune diseases or viral infections such as in acute and post-acute or Long COVID-19.

Tractography-based automated identification of the retinogeniculate visual pathway with novel microstructure-informed supervised contrastive learning.

The retinogeniculate visual pathway (RGVP) is responsible for carrying visual information from the retina to the lateral geniculate nucleus. Identification and visualization of the RGVP are important in studying the anatomy of the visual system and can inform the treatment of related brain diseases. Diffusion MRI (dMRI) tractography is an advanced imaging method that uniquely enables in vivo mapping of the 3D trajectory of the RGVP. Currently, identification of the RGVP from tractography data relies on expert (manual) selection of tractography streamlines, which is time-consuming, has high clinical and expert labor costs, and is affected by inter-observer variability. In this paper, we present a novel deep learning framework, DeepRGVP , to enable fast and accurate identification of the RGVP from dMRI tractography data. We design a novel microstructure-informed supervised contrastive learning method that leverages both streamline label and tissue microstructure information to determine positive and negative pairs. We propose a simple and successful streamline-level data augmentation method to address highly imbalanced training data, where the number of RGVP streamlines is much lower than that of non-RGVP streamlines. We perform comparisons with several state-of-the-art deep learning methods that were designed for tractography parcellation, and we show superior RGVP identification results using DeepRGVP. In addition, we demonstrate a good generalizability of DeepRGVP to dMRI tractography data from neurosurgical patients with pituitary tumors and we show DeepRGVP can successfully identify RGVPs despite the effect of lesions affecting the RGVPs. Overall, our study shows the high potential of using deep learning to automatically identify the RGVP.

Reconstructing the somatotopic organization of the corticospinal tract remains a challenge for modern tractography methods.

The corticospinal tract (CST) is a critically important white matter fiber tract in the human brain that enables control of voluntary movements of the body. The CST exhibits a somatotopic organization, which means that the motor neurons that control specific body parts are arranged in order within the CST. Diffusion magnetic resonance imaging (MRI) tractography is increasingly used to study the anatomy of the CST. However, despite many advances in tractography algorithms over the past decade, modern, state-of-the-art methods still face challenges. In this study, we compare the performance of six widely used tractography methods for reconstructing the CST and its somatotopic organization. These methods include constrained spherical deconvolution (CSD) based probabilistic (iFOD1) and deterministic (SD-Stream) methods, unscented Kalman filter (UKF) tractography methods including multi-fiber (UKF2T) and single-fiber (UKF1T) models, the generalized q-sampling imaging (GQI) based deterministic tractography method, and the TractSeg method. We investigate CST somatotopy by dividing the CST into four subdivisions per hemisphere that originate in the leg, trunk, hand, and face areas of the primary motor cortex. A quantitative and visual comparison is performed using diffusion MRI data (N = 100 subjects) from the Human Connectome Project. Quantitative evaluations include the reconstruction rate of the eight anatomical subdivisions, the percentage of streamlines in each subdivision, and the coverage of the white matter-gray matter (WM-GM) interface. CST somatotopy is further evaluated by comparing the percentage of streamlines in each subdivision to the cortical volumes for the leg, trunk, hand, and face areas. Overall, UKF2T has the highest reconstruction rate and cortical coverage. It is the only method with a significant positive correlation between the percentage of streamlines in each subdivision and the volume of the corresponding motor cortex. However, our experimental results show that all compared tractography methods are biased toward generating many trunk streamlines (ranging from 35.10% to 71.66% of total streamlines across methods). Furthermore, the coverage of the WM-GM interface in the largest motor area (face) is generally low (under 40%) for all compared tractography methods. Different tractography methods give conflicting results regarding the percentage of streamlines in each subdivision and the volume of the corresponding motor cortex, indicating that there is generally no clear relationship, and that reconstruction of CST somatotopy is still a large challenge. Overall, we conclude that while current tractography methods have made progress toward the well-known challenge of improving the reconstruction of the lateral projections of the CST, the overall problem of performing a comprehensive CST reconstruction, including clinically important projections in the lateral (hand and face areas) and medial portions (leg area), remains an important challenge for diffusion MRI tractography.

From 'mental fog' to post-acute COVID-19 syndrome's executive function alteration: Implications for clinical approach.

A common symptom of the neuropsychiatric Post-Acute COVID-19 syndrome (neuro-PACS) is the so called 'brain fog'. Patients describe the brain fog as problems with attention, memory and mental fatigue. Brain fog is experienced by 9-55% of people for months after having contracted SARS-CoV-2 virus. Several theories have been proposed to explain PACS's brain fog, including a neuroinflammatory hypothesis, but the hypothesis remains to be proven. Here, we examined inflammatory and immunological blood profile in a cohort of patients with PACS to investigate the association between executive functions and blood inflammatory markers. Executive function was assessed by the Trail Making Test (TMT) Part A and Part B, as well as the Barkley Deficits in Executive Functioning Scale (BDEFS), in 71 patients (36 men), average age of 40 years (range: 15-82, SD: 15.7). Impairment in executive functioning (BDEFS scores and TMT B scores) correlated with increased levels of Interleukin-6 (IL-6), fibrinogen and ferritin. Moreover, elevated levels of Il-6, fibrinogen, ferritin, tumor necrosis factor-alpha and C-reactive protein have been observed in PACS. These findings demonstrate that PACS is characterized by the presence of an immuno-inflammatory process, which is associated with diminished executive functioning. Here, we argue in favour of a shift from the non-descriptive definition of 'mental fog' to a characterization of a subtype of PACS, associated with alteration in executive functioning. Implication for clinical settings and prevention are discussed.

Investigation of brain iron in anorexia nervosa, a quantitative susceptibility mapping study.

BACKGROUND: Anorexia nervosa (AN) is a potentially fatal psychiatric condition, associated with structural brain changes such as gray matter volume loss. The pathophysiological mechanisms for these changes are not yet fully understood. Iron is a crucial element in the development and function of the brain. Considering the systemic alterations in iron homeostasis in AN, we hypothesized that brain iron would be altered as a possible factor associated with structural brain changes in AN. METHODS: In this study, we used quantitative susceptibility mapping (QSM) magnetic resonance imaging to investigate brain iron in current AN (c-AN) and weight-restored AN compared with healthy individuals. Whole-brain voxel wise comparison was used to probe areas with possible group differences. Further, the thalamus, caudate nucleus, putamen, nucleus accumbens, hippocampus, and amygdala were selected as the regions of interest (ROIs) for ROI-based comparison of mean QSM values. RESULTS: Whole-brain voxel-wise and ROI-based comparison of QSM did not reveal any differences between groups. Exploratory analyses revealed a correlation between higher regional QSM (higher iron) and lower body mass index, higher illness severity, longer illness duration, and younger age at onset in the c-AN group. CONCLUSIONS: This study did not find evidence of altered brain iron in AN compared to healthy individuals. However, the correlations between clinical variables and QSM suggest a link between brain iron and weight status or biological processes in AN, which warrants further investigation.

Superficial white matter analysis: An efficient point-cloud-based deep learning framework with supervised contrastive learning for consistent tractography parcellation across populations and dMRI acquisitions.

Diffusion MRI tractography is an advanced imaging technique that enables in vivo mapping of the brain's white matter connections. White matter parcellation classifies tractography streamlines into clusters or anatomically meaningful tracts. It enables quantification and visualization of whole-brain tractography. Currently, most parcellation methods focus on the deep white matter (DWM), whereas fewer methods address the superficial white matter (SWM) due to its complexity. We propose a novel two-stage deep-learning-based framework, Superficial White Matter Analysis (SupWMA), that performs an efficient and consistent parcellation of 198 SWM clusters from whole-brain tractography. A point-cloud-based network is adapted to our SWM parcellation task, and supervised contrastive learning enables more discriminative representations between plausible streamlines and outliers for SWM. We train our model on a large-scale tractography dataset including streamline samples from labeled long- and medium-range (over 40 mm) SWM clusters and anatomically implausible streamline samples, and we perform testing on six independently acquired datasets of different ages and health conditions (including neonates and patients with space-occupying brain tumors). Compared to several state-of-the-art methods, SupWMA obtains highly consistent and accurate SWM parcellation results on all datasets, showing good generalization across the lifespan in health and disease. In addition, the computational speed of SupWMA is much faster than other methods.

In Vivo 7-Tesla MRI Investigation of Brain Iron and Its Metabolic Correlates in Chronic Schizophrenia.

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

The use of hydrogel-delivered extracellular vesicles in recovery of motor function in stroke: a testable experimental hypothesis for clinical translation including behavioral and neuroimaging assessment approaches.

Neural tissue engineering, nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system (CNS) repair. It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes, making development of CNS therapeutics challenging. Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society, it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels. Extracellular vesicles (EVs), also known as exosomes, when derived from mesenchymal stem cells, are one of the most promising approaches that have been attempted thus far, as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation. At the same time, advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur, as well as the release of biomolecules facilitating or inducing the reparative processes. This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels. The rationale behind this hypothesis is presented, analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain. This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur. Finally, the importance of including non-human primate models in the clinical translation pipeline, as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive, in vivo, quantifiable imaging-based biomarkers for CNS repair are discussed, aiming for more effective and safe clinical translation of such regenerative therapies to humans.

Human Cochlear Nucleus on 7 Tesla Diffusion Tensor Imaging: Insights Into Micro-anatomy and Function for Auditory Brainstem Implant Surgery.

OBJECTIVE: The cochlear nucleus (CN) is the target of the auditory brainstem implant (ABI). Most ABI candidates have Neurofibromatosis Type 2 (NF2) and distorted brainstem anatomy from bilateral vestibular schwannomas. The CN is difficult to characterize as routine structural MRI does not resolve detailed anatomy. We hypothesize that diffusion tensor imaging (DTI) enables both in vivo localization and quantitative measurements of CN morphology. STUDY DESIGN: We analyzed 7 Tesla (T) DTI images of 100 subjects (200 CN) and relevant anatomic structures using an MRI brainstem atlas with submillimetric (50 µm) resolution. SETTING: Tertiary referral center. PATIENTS: Young healthy normal hearing adults. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: Diffusion scalar measures such as fractional anisotropy (FA), mean diffusivity (MD), mode of anisotropy (Mode), principal eigenvectors of the CN, and the adjacent inferior cerebellar peduncle (ICP). RESULTS: The CN had a lamellar structure and ventral-dorsal fiber orientation and could be localized lateral to the inferior cerebellar peduncle (ICP). This fiber orientation was orthogonal to tracts of the adjacent ICP where the fibers run mainly caudal-rostrally. The CN had lower FA compared to the medial aspect of the ICP (0.44 ±â€Š0.09 vs. 0.64 ±â€Š0.08, p < 0.001). CONCLUSIONS: 7T DTI enables characterization of human CN morphology and neuronal substructure. An ABI array insertion vector directed more caudally would better correspond to the main fiber axis of CN. State-of-the-art DTI has implications for ABI preoperative planning and future image guidance-assisted placement of the electrode array.

A carotid bifurcation pseudoaneurysm treated endovascularly in a patient with irradiated neck.

A carotid artery pseudoaneurysm in an irradiated neck is a rare entity with possible devastating results and management should be multidisciplinary. We present a successful endovascular treatment of a late carotid artery pseudoaneurysm following patch endarterectomy and cervical radiotherapy.

An anatomically curated fiber clustering white matter atlas for consistent white matter tract parcellation across the lifespan.

This work presents an anatomically curated white matter atlas to enable consistent white matter tract parcellation across different populations. Leveraging a well-established computational pipeline for fiber clustering, we create a tract-based white matter atlas including information from 100 subjects. A novel anatomical annotation method is proposed that leverages population-based brain anatomical information and expert neuroanatomical knowledge to annotate and categorize the fiber clusters. A total of 256 white matter structures are annotated in the proposed atlas, which provides one of the most comprehensive tract-based white matter atlases covering the entire brain to date. These structures are composed of 58 deep white matter tracts including major long range association and projection tracts, commissural tracts, and tracts related to the brainstem and cerebellar connections, plus 198 short and medium range superficial fiber clusters organized into 16 categories according to the brain lobes they connect. Potential false positive connections are annotated in the atlas to enable their exclusion from analysis or visualization. In addition, the proposed atlas allows for a whole brain white matter parcellation into 800 fiber clusters to enable whole brain connectivity analyses. The atlas and related computational tools are open-source and publicly available. We evaluate the proposed atlas using a testing dataset of 584 diffusion MRI scans from multiple independently acquired populations, across genders, the lifespan (1 day-82 years), and different health conditions (healthy control, neuropsychiatric disorders, and brain tumor patients). Experimental results show successful white matter parcellation across subjects from different populations acquired on multiple scanners, irrespective of age, gender or disease indications. Over 99% of the fiber tracts annotated in the atlas were detected in all subjects on average. One advantage in terms of robustness is that the tract-based pipeline does not require any cortical or subcortical segmentations, which can have limited success in young children and patients with brain tumors or other structural lesions. We believe this is the first demonstration of consistent automated white matter tract parcellation across the full lifespan from birth to advanced age.

17ß-estradiol differentially regulates stress circuitry activity in healthy and depressed women.

Many regions within stress neurocircuitry, including the anterior hypothalamus, amygdala, hippocampus, and medial prefrontal cortex, are densely populated with sex steroid receptors. Substantial evidence from animal studies indicates that the gonadal hormone 17ß-estradiol (E2) impacts the structure and function of these regions, but human studies are limited. Characterizing estradiol's role in stress circuitry in vivo in humans may have important clinical implications given the comorbidity between major depressive disorder (MDD), stress circuitry dysfunction and endocrine dysregulation. In this study, we determined estradiol's role in modulating activity within cortical and subcortical stress circuitry regions in healthy and MDD women. Subjects were part of a population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in E2 during the menstrual cycle, we conducted a within-person repeated-measures functional neuroimaging study in which 15 women with recurrent MDD, in remission, and 15 healthy control women underwent hormonal evaluations, behavioral testing, and fMRI scanning on two occasions, under low and high E2 conditions. Subjects completed an fMRI scan while undergoing a mild visual stress challenge that reliably activated stress neural circuitry. Results demonstrate that E2 modulates activity across key stress circuitry regions, including bilateral amygdala, hippocampus, and hypothalamus. In healthy women, robust task-evoked BOLD signal changes observed under low E2 conditions were attenuated under high E2 conditions. This hormonal capacity to regulate activity in stress circuitry was not observed in MDD women, despite their remitted status, suggesting that dysregulation of gonadal hormone function may be a characteristic trait of the disease. These findings serve to deepen our understanding of estradiol's actions in the healthy brain and the neurobiological mechanisms that may underlie the pronounced sex difference in MDD risk.

Cannabis use is quantitatively associated with nucleus accumbens and amygdala abnormalities in young adult recreational users.

Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization.

Investigation of the dose- and time-dependence of the induction of different types of cell death in a small­cell lung cancer cell line: Implementation of the repairable-conditionally repairable model.

The purpose of this study was to quantify and model various types of cell death for a small-cell lung cancer (SCLC) cell line (U1690) after exposure to a 137Cs source and as well as to compare the linear-quadratic (LQ) and repairable-conditionally repairable model (RCR). This study is based on four different experiments that were taken place at Cancer Centrum Karolinska (CCK). A human small-cell lung cancer (SCLC) cell line after the exposure to a 137Cs source was used for the extraction of the clonogenic cell survival curve. Additionally, for the determination and quantification of various modes of cell death the method of fluorescence staining was implemented, where the cell deaths were categorized based on morphological characteristics. The percentage of cells in each phase of the cell cycle was investigated with flow cytometry analysis. The quantification of senescent cells was performed by staining the samples with senescence-associated ß-galactosidase (SA-ß-Gal) solution and then scoring as senescent cells those that had incorporated the substance. These data were introduced into a maximum likelihood fitting to calculate the best estimates of the parameters used by the examined model. In this model, the modes of cell death are divided into three categories: apoptotic, senescent and other types of cell death (necrotic/apoptotic, necrotic, micronuclei and giant). In the clonogenic cell survival assay, the fitting of the RCR model gives a χ(2)-value of 6.10 whereas for the LQ model became 9.61. In the fluorescence microscopy and senescence assay, the probability of the three different modes of cell death on day 2 seems to increases with a dose up to about 10 Gy where there is saturation. On day 7 a significant induction of apoptosis in a dose- and time-dependent manner was evident, whereas senescence was slightly increased in response to dose but not to time. As for the 'other types of cell death' mode on day 7 showed a higher probability than the one on day 2 and as well as a prominent dose-dependence. The RCR model fits better to the experimental data than the LQ model. On day 2 there is a slight increase of the apoptotic and senescent probability with dose. On the other hand, on day 7 the shape of the curve of apoptosis differs and a sigmoidal increase with dose is observed. At both time-points, the present model fits the data reasonably well. Due to the fact that the clonogenic survival does not coincide with the one extracted from the fluorescence microscopy, a more accurate way to quantify cell death needs to be used, e.g. computerized video time-lapse (CVTL).

Metabolic activity in the insular cortex and hypothalamus predicts hot flashes: an FDG-PET study.

CONTEXT: Hot flashes are a common side effect of adjuvant endocrine therapies (AET; leuprolide, tamoxifen, aromatase inhibitors) that reduce quality of life and treatment adherence in breast cancer patients. Because hot flashes affect only some women, preexisting neurobiological traits might predispose to their development. Previous studies have implicated the insula during the perception of hot flashes and the hypothalamus in thermoregulatory dysfunction. OBJECTIVE: The aim of the study was to understand whether neurobiological factors predict hot flashes. DESIGN: [18F]-Fluorodeoxyglucose (FDG) positron emission tomography (PET) brain scans coregistered with structural magnetic resonance imaging were used to determine whether metabolic activity in the insula and hypothalamic thermoregulatory and estrogen-feedback regions measured before and in response to AET predict hot flashes. Findings were correlated with CYP2D6 genotype because of CYP2D6 polymorphism associations with tamoxifen-induced hot flashes. OUTCOME MEASURES: We measured regional cerebral metabolic rate of glucose uptake (rCMRglu) in the insula and hypothalamus on FDG-PET. RESULTS: Of 18 women without hot flashes who began AET, new-onset hot flashes were reported by 10 (55.6%) and were detected objectively in nine (50%) participants. Prior to the use of all AET, rCMRglu in the insula (P ≤ 0.01) and hypothalamic thermoregulatory (P = 0.045) and estrogen-feedback (P = 0.007) regions was lower in women who reported developing hot flashes. In response to AET, rCMRglu was further reduced in the insula in women developing hot flashes (P ≤ 0.02). Insular and hypothalamic rCMRglu levels were lower in intermediate than extensive CYP2D6 metabolizers. CONCLUSIONS: Trait neurobiological characteristics predict hot flashes. Genetic variability in CYP2D6 may underlie the neurobiological predisposition to hot flashes induced by AET.

Age-related changes in the corpus callosum in early-onset bipolar disorder assessed using volumetric and cross-sectional measurements.

Corpus callosum (CC) area abnormalities have been reported in magnetic resonance imaging (MRI) studies of adults and youths with bipolar disorder (BPD), suggesting interhemispheric communication may be abnormal in BPD and may be present early in the course of illness and affect normal neuromaturation of this structure throughout the lifecycle. Neuroimaging scans from 44 youths with DSM-IV BPD and 22 healthy controls (HC) were analyzed using cross-sectional area measurements and a novel method of volumetric parcellation. Univariate analyses of variance were conducted on CC subregions using both volume and traditional area measurements. Youths with BPD had smaller middle and posterior callosal regions, and reduced typical age-related increases in CC size. The cross-sectional area and novel volumetric methodologies resulted in similar findings. Future longitudinal assessments of CC development would track the evolution of callosal abnormalities in youths with BPD and allow exploration of the functional significance of these findings.

Association of a polymorphism near CREB1 with differential aversion processing in the insula of healthy participants.

CONTEXT: Previous functional neuroimaging studies have identified a network of brain regions that process aversive stimuli, including anger. A polymorphism near the cyclic adenosine monophosphate response element binding protein gene (CREB1) has recently been associated with greater self-reported effort at anger control as well as risk for antidepressant treatment-emergent suicidality in men with major depressive disorder, but its functional effects have not been studied. OBJECTIVE: To determine whether this genetic variant is associated with altered brain processing of and behavioral avoidance responses to angry facial expressions. DESIGN AND PARTICIPANTS: A total of 28 white participants (mean age, 29.2 years; 13 women) were screened using the Structured Clinical Interview for DSM-IV to exclude any lifetime Axis I psychiatric disorder and were genotyped for rs4675690, a single-nucleotide polymorphism near CREB1. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent signal by functional magnetic resonance imaging in the amygdala, insula, anterior cingulate, and orbitofrontal cortex during passive viewing of photographs of faces with emotional expressions. To measure approach and avoidance responses to anger, an off-line key-press task that traded effort for viewing time assessed valuation of angry faces compared with other expressions. RESULTS: The CREB1-linked single-nucleotide polymorphism was associated with significant differential activation in an extended neural network responding to angry and other facial expressions. The CREB1-associated insular activation was coincident with activation associated with behavioral avoidance of angry faces. CONCLUSIONS: A polymorphism near CREB1 is associated with responsiveness to angry faces in a brain network implicated in processing aversion. Coincident activation in the left insula is further associated with behavioral avoidance of these stimuli.

The incidence of retained fetal bone revealed in 2000 diagnostic hysteroscopies.

Three of 2000 diagnostic hysteroscopies revealed residual fetal bony fragments in women with abnormal uterine bleeding. Removal of bony fragments by hysteroscopy is associated with therapeutic success.