The BigBrainWarp toolbox for integration of BigBrain 3D histology with multimodal neuroimaging.

Neuroimaging stands to benefit from emerging ultrahigh-resolution 3D histological atlases of the human brain; the first of which is 'BigBrain'. Here, we review recent methodological advances for the integration of BigBrain with multi-modal neuroimaging and introduce a toolbox, 'BigBrainWarp', that combines these developments. The aim of BigBrainWarp is to simplify workflows and support the adoption of best practices. This is accomplished with a simple wrapper function that allows users to easily map data between BigBrain and standard MRI spaces. The function automatically pulls specialised transformation procedures, based on ongoing research from a wide collaborative network of researchers. Additionally, the toolbox improves accessibility of histological information through dissemination of ready-to-use cytoarchitectural features. Finally, we demonstrate the utility of BigBrainWarp with three tutorials and discuss the potential of the toolbox to support multi-scale investigations of brain organisation.

Creating a Comprehensive Research Platform for Surgical Technique and Operative Outcome in Primary Brain Tumor Neurosurgery.

BACKGROUND: The operative environment poses many challenges to studying the relationship between surgical acts and patient outcomes in intracranial oncological neurosurgery. We sought to develop a framework in which neurosurgical performance and extent of resection could be precisely quantified in a controlled setting. METHODS: The stiffness of an alginate hydrogel-based tumor was modified with differing concentrations of the cross-linking agent calcium sulfate until biomechanical properties similar to those of human primary brain tumors measured at resection were achieved. The artificial tumor was subsequently incorporated into an ex-vivo animal brain as a final model. Magnetic resonance imaging enhancement and ultraviolet fluorescence was achieved by incorporating gadolinium and fluorescein solution, respectively. Video recordings from the operative microscope, ceiling cameras, and instrument-mounted fiducial markers within a surgical suite environment captured operative performance. RESULTS: A total of 24 rheometer measurements were conducted on alginate hydrogels containing 10-, 11-, and 12-mM concentrations of calcium sulfate. Sixty-eight stiffness measurements were conducted on eight patient tumor samples. No differences were found between the alginate and brain tumor stiffness values [Kruskal-Wallis χ2(4) = 9.187; P = 0.057]. Tumor was identified using ultraviolet fluorescence and ultrasonography. The volume and location of the resected white and gray matter and residual tumor could be quantified in 0.003-mm3 increments using a 7T magnetic resonance imaging coil. Ultrasonic aspirator and bipolar electrocautery movement data were successfully transformed into performance metrics. CONCLUSION: The developed framework can offer clinicians, learners, and researchers the ability to perform operative rehearsal, teaching, and studies involving brain tumor surgery in a controlled laboratory environment and represents a crucial step in the understanding and training of expertise in neurosurgery.

White matter microstructure is associated with hyperactive/inattentive symptomatology and polygenic risk for attention-deficit/hyperactivity disorder in a population-based sample of adolescents.

Few studies have investigated the link between putative biomarkers of attention-deficit/hyperactivity disorder (ADHD) symptomatology and genetic risk for ADHD. To address this, we investigate the degree to which ADHD symptomatology is associated with white matter microstructure and cerebral cortical thickness in a large population-based sample of adolescents. Critically, we then test the extent to which multimodal correlates of ADHD symptomatology are related to ADHD polygenic risk score (PRS). Neuroimaging, genetic, and behavioral data were obtained from the IMAGEN study. A dimensional ADHD composite score was derived from multi-informant ratings of ADHD symptomatology. Using tract-based spatial statistics, whole brain voxel-wise regressions between fractional anisotropy (FA) and ADHD composite score were calculated. Local cortical thickness was regressed on ADHD composite score. ADHD PRS was based on a very recent genome-wide association study, and calculated using PRSice. ADHD composite score was negatively associated with FA in several white matter pathways, including bilateral superior and inferior longitudinal fasciculi (p < 0.05, corrected). ADHD composite score was negatively associated with orbitofrontal cortical thickness (p < 0.05, corrected). The ADHD composite score was correlated with ADHD PRS (p < 0.001). FA correlates of ADHD symptomatology were significantly associated with ADHD PRS, whereas cortical thickness correlates of ADHD symptomatology were unrelated to ADHD PRS. Variation in hyperactive/inattentive symptomatology was associated with white matter microstructure, which, in turn, was related to ADHD PRS. Results suggest that genetic risk for ADHD symptomatology may be tied to biological processes affecting white matter microstructure.

Detection and clinical correlation of leukocortical lesions in pediatric-onset multiple sclerosis on multi-contrast MRI.

OBJECTIVE: To determine the frequency of cortical lesions (CLs) in patients with pediatric-onset multiple sclerosis (POMS) using multi-contrast magnetic resonance imaging (MRI), and the relationship between frontal CL load and upper limb dexterity assessed with the Nine-Hole Peg Test (9-HPT). METHODS: Participants completed the 9-HPT and were imaged on a 3T MRI scanner to collect T1-weighted three-dimensional (3D) magnetization prepared rapid gradient echo (MPRAGE), proton density-weighted, T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. CLs were manually segmented using all MRI contrasts. RESULTS: We enrolled 24 participants with POMS (mean (standard deviation) age at first symptom: 13.3 (±2.7) years; mean age at scan: 18.8 (±3) years; mean disease duration of 5 (±3.2) years). A total of 391 CLs (mean, 16.3 ± 27.2; median, 7) were identified in 19 of 24 POMS patients (79%). The total number of CLs was positively associated with white matter lesion volume ( p = 0.04) but not with thalamic volume, age at the time of the scan, or disease duration. The number of frontal CLs was associated with slower performance on the 9-HPT ( p = 0.05). CONCLUSION: Multi-contrast 3T MRI led to a high rate of CL detection, demonstrating that cortical pathology occurs even in pediatric-onset disease. Frontal lobe CL count was associated with reduced manual dexterity, indicating that these CLs are clinically relevant.

Interaction driven enhancement of depth perception in angiographic volumes.

User interaction has the potential to greatly facilitate the exploration and understanding of 3D medical images for diagnosis and treatment. However, in certain specialized environments such as in an operating room (OR), technical and physical constraints such as the need to enforce strict sterility rules, make interaction challenging. In this paper, we propose to facilitate the intraoperative exploration of angiographic volumes by leveraging the motion of a tracked surgical pointer, a tool that is already manipulated by the surgeon when using a navigation system in the OR. We designed and implemented three interactive rendering techniques based on this principle. The benefit of each of these techniques is compared to its non-interactive counterpart in a psychophysics experiment where 20 medical imaging experts were asked to perform a reaching/targeting task while visualizing a 3D volume of angiographic data. The study showed a significant improvement of the appreciation of local vascular structure when using dynamic techniques, while not having a negative impact on the appreciation of the global structure and only a marginal impact on the execution speed. A qualitative evaluation of the different techniques showed a preference for dynamic chroma-depth in accordance with the objective metrics but a discrepancy between objective and subjective measures for dynamic aerial perspective and shading.

White matter degeneration profile in the cognitive cortico-subcortical tracts in Parkinson's disease.

BACKGROUND: In Parkinson's disease cognitive impairment is an early nonmotor feature, but it is still unclear why some patients are able to maintain their cognitive performance at normal levels, as quantified by neuropsychological tests, whereas others cannot. The objectives of this study were to perform a cross-sectional study and analyze the white matter changes in the cognitive and motor bundles in patients with Parkinson's disease. METHODS: Sixteen Parkinson's disease patients with normal cognitive performance, 19 with mild cognitive impairment (based on their performance of 1.5 standard deviations below the healthy population mean), and 16 healthy controls were compared with respect to their tractography patterns between the cortical cognitive / motor regions and subcortical structures, using high angular resolution diffusion imaging and constrained spherical deconvolution computation. RESULTS: Motor bundles showed decreased apparent fiber density in both PD groups, associated with a significant increase in diffusivity metrics, number of reconstructed streamlines, and track volumes, compared with healthy controls. By contrast, in the cognitive bundles, decreased fiber density in both Parkinson's groups was compounded by the absence of changes in diffusivity in patients with normal cognition, whereas patients with cognitive impairment had increased diffusivity metrics, lower numbers of reconstructed streamlines, and lower track volumes. CONCLUSIONS: Both PD groups showed similar patterns of white matter neurodegeneration in the motor bundles, whereas cognitive bundles showed a distinct pattern: Parkinson's patients with normal cognition had white matter diffusivity metrics similar to healthy controls, whereas in patients with cognitive impairment white matter showed a neurodegeneration pattern. © 2018 International Parkinson and Movement Disorder Society.

Distance sonification in image-guided neurosurgery.

Image-guided neurosurgery, or neuronavigation, has been used to visualise the location of a surgical probe by mapping the probe location to pre-operative models of a patient's anatomy. One common limitation of this approach is that it requires the surgeon to divert their attention away from the patient and towards the neuronavigation system. In order to improve this type of application, the authors designed a system that sonifies (i.e. provides audible feedback of) distance information between a surgical probe and the location of the anatomy of interest. A user study (n = 15) was completed to determine the utility of sonified distance information within an existing neuronavigation platform (Intraoperative Brain Imaging System (IBIS) Neuronav). The authors' results were consistent with the idea that combining auditory distance cues with existing visual information from image-guided surgery systems may result in greater accuracy when locating specified points on a pre-operative scan, thereby potentially reducing the extent of the required surgical openings, as well as potentially increasing the precision of individual surgical tasks. Further, the authors' results were also consistent with the hypothesis that combining auditory and visual information reduces the perceived difficulty in locating a target location within a three-dimensional volume.

Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive behaviors that typically emerge by 24 months of age. To develop effective early interventions that can potentially ameliorate the defining deficits of ASD and improve long-term outcomes, early detection is essential. Using prospective neuroimaging of 59 6-month-old infants with a high familial risk for ASD, we show that functional connectivity magnetic resonance imaging correctly identified which individual children would receive a research clinical best-estimate diagnosis of ASD at 24 months of age. Functional brain connections were defined in 6-month-old infants that correlated with 24-month scores on measures of social behavior, language, motor development, and repetitive behavior, which are all features common to the diagnosis of ASD. A fully cross-validated machine learning algorithm applied at age 6 months had a positive predictive value of 100% [95% confidence interval (CI), 62.9 to 100], correctly predicting 9 of 11 infants who received a diagnosis of ASD at 24 months (sensitivity, 81.8%; 95% CI, 47.8 to 96.8). All 48 6-month-old infants who were not diagnosed with ASD were correctly classified [specificity, 100% (95% CI, 90.8 to 100); negative predictive value, 96.0% (95% CI, 85.1 to 99.3)]. These findings have clinical implications for early risk assessment and the feasibility of developing early preventative interventions for ASD.

The developmental relationship between DHEA and visual attention is mediated by structural plasticity of cortico-amygdalar networks.

Humans and the great apes are the only species demonstrated to exhibit adrenarche, a key developmental event leading to increased production of dehydroepiandrosterone (DHEA), suggesting that this hormone may play an important evolutionary role. Similarly, visual attention networks have been shown to evolve in a human-specific manner, with some anatomical connections and elements of cortical organization exclusive to our species. Existing studies of human brain development support the notion that DHEA shows significant uptake in cortical structures and the amygdala, and as such, could be involved in the bottom-up regulation of visual attention. Here we examined associations between DHEA, structural covariance of the amygdala with whole-brain cortical thickness, and tests of visual attention, in a longitudinal sample of typically developing children and adolescents 6-22 years of age. We found that DHEA predicted covariance between amygdalar volume and the left occipital pole, right somatosensory parietal cortex and right anterior cingulate cortex. Amygdala-occipital covariance predicted visual awareness; amygdala-parietal covariance predicted visuo-motor dexterity and processing speed; amygdala-prefrontal covariance predicted global attentional impairment. Further, effects of DHEA were above and beyond those of age and sex, as well as distinct from those of pubertal stage, estradiol and testosterone. These findings support the notion that DHEA may play a unique role in shaping amygdala-dependent cortical plasticity and in regulating 'bottom-up' visual attention processes from childhood to young adulthood.

A stereotaxic, population-averaged T1w ovine brain atlas including cerebral morphology and tissue volumes.

Standard stereotaxic reference systems play a key role in human brain studies. Stereotaxic coordinate systems have also been developed for experimental animals including non-human primates, dogs, and rodents. However, they are lacking for other species being relevant in experimental neuroscience including sheep. Here, we present a spatial, unbiased ovine brain template with tissue probability maps (TPM) that offer a detailed stereotaxic reference frame for anatomical features and localization of brain areas, thereby enabling inter-individual and cross-study comparability. Three-dimensional data sets from healthy adult Merino sheep (Ovis orientalis aries, 12 ewes and 26 neutered rams) were acquired on a 1.5 T Philips MRI using a T1w sequence. Data were averaged by linear and non-linear registration algorithms. Moreover, animals were subjected to detailed brain volume analysis including examinations with respect to body weight (BW), age, and sex. The created T1w brain template provides an appropriate population-averaged ovine brain anatomy in a spatial standard coordinate system. Additionally, TPM for gray (GM) and white (WM) matter as well as cerebrospinal fluid (CSF) classification enabled automatic prior-based tissue segmentation using statistical parametric mapping (SPM). Overall, a positive correlation of GM volume and BW explained about 15% of the variance of GM while a positive correlation between WM and age was found. Absolute tissue volume differences were not detected, indeed ewes showed significantly more GM per bodyweight as compared to neutered rams. The created framework including spatial brain template and TPM represent a useful tool for unbiased automatic image preprocessing and morphological characterization in sheep. Therefore, the reported results may serve as a starting point for further experimental and/or translational research aiming at in vivo analysis in this species.

A new template to study callosal growth shows specific growth in anterior and posterior regions of the corpus callosum in early childhood.

Most of the studies conducted on the development of the corpus callosum (CC) have been limited to a relatively simple assessment of callosal area, providing an estimation of the size of the CC in two dimensions rather than its actual measurement. The goal of this study was to revisit callosal development in childhood and adolescence by using a three-dimensional (3D) magnetic resonance imaging template of the CC that considers the horizontal width of the CC and compares this with the two-dimensional (2D) callosal area. We mapped callosal growth in a large sample of youths followed longitudinally (N = 370 at T1; N = 304 at T2; and N = 246 at T3). Both techniques were based on a five-section subdivision of the CC. The results obtained with the 3D method revealed that the rate of CC growth over a 4-year period in the rostrum, the genu, the anterior body and the splenium was significantly higher in the youngest age group (< 7 years) than in older groups, indicating an intense period of development in early childhood for the anterior and posterior parts of the CC. Similar results were obtained when 2D callosal area was used for the anterior and posterior parts of the CC. However, divergent results were found in the mid-body and the caudal body of the CC. As shown by differences between 2D estimations and actual 3D measurements of callosal growth, our study highlights the importance of considering the horizontal width in measuring developmental changes in the CC.

Establishing magnetic resonance images orientation for the EADC-ADNI manual hippocampal segmentation protocol.

BACKGROUND AND PURPOSE: An effort to define and validate a Harmonized Protocol for standard hippocampal segmentation is being carried out. We wished to estimate the effect of magnetic resonance image (MRI) spatial orientation on manual hippocampal segmentations to define optimal standard orientation of MRIs for hippocampal volumetry. METHODS: Three expert tracers segmented twice the hippocampi of 10 ADNI subjects on MRI slices oriented perpendicular to the anterior-posterior commissure (AC-PC) line and the long hippocampal axes plane, following internationally harmonized landmarks. We computed intra and interrater reliability figures for total volumes and similarity coefficients. RESULTS: Total volume reliability was similar for both orientations. Similarity coefficients were significantly higher for the AC-PC orientation (exact P = 0.002). DISCUSSION: These data show that AC-PC orientation is slightly more reliable for manual segmentations, possibly due to better visualization of the cerebrospinal fluid spaces separating hippocampal head and amygdala. A Delphi panel of experts has used these data to decide on the optimal orientation for a Harmonized Protocol for hippocampal segmentation.

Interhemispheric coupling improves the brain's ability to perform low cognitive demand tasks in Alzheimer's disease and high cognitive demand tasks in normal aging.

OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects the corpus callosum (CC), which plays a key role in interhemispheric coupling in high-demand conditions. Using 3D callosal measurements and a letter-matching paradigm, this 2-part study investigated the neural substrate of interhemispheric coupling in individuals with AD or amnestic mild cognitive impairment (a-MCI) and age-matched healthy individuals (HC). METHOD: Thirty-three right-handed participants were MRI scanned to measure the volume of the CC in 5 sections. In Study 1, AD, a-MCI, and HC individuals performed a low-demand perceptual letter shape-matching task (e.g., A-A); in Study 2, a-MCI and HC individuals performed a "case-sensitive" letter-matching task (Study 2A) and a "load-sensitive" letter-matching task (Study 2B). RESULTS: The results showed a positive correlation between Response Times and the midbody of the CC at the lowest cognitive demand level (Study 1) in participants with AD, and the total CC, midbody, caudal body, and isthmus of the CC at high cognitive demand levels (Study 2A) in normal aging. The volume of the anterior part of the CC was significantly negatively correlated with the interhemispheric behavioral indices for the a-MCI group (Study 1 and Study 2B). CONCLUSION: This study provides evidence that interhemispheric coupling may constitute a flexible mechanism that can improve the brain's ability to meet processing demands for low cognitive demand in AD and for high cognitive demand in normal aging.

Changes in cortical thickness during the course of illness in schizophrenia.

CONTEXT: Whether cortical thickness changes in schizophrenia over time are more pronounced relative to the changes that can be attributed to normal aging has not been studied. OBJECTIVE: To compare patients with schizophrenia and healthy control participants on cortical thickness change. DESIGN: A 5-year longitudinal study comparing schizophrenic patients and healthy controls using 2 magnetic resonance images of the brain. SETTING: Patients were recruited from the Department of Psychiatry at the University Medical Centre Utrecht and from other psychiatric hospitals in the Netherlands. Healthy controls were recruited via advertisement in newspapers and notice boards. PARTICIPANTS: Ninety-six schizophrenic patients and 113 healthy controls aged 16 to 56 years. MAIN OUTCOME MEASURES: Cortical thickness and change in cortical thickness on a vertex-by-vertex basis across the cortical mantle, measures of functional and symptomatic outcome, and cumulative intake of antipsychotics during the scan interval. RESULTS: At baseline, the schizophrenic patients had thinner left orbitofrontal and right parahippocampal and superior temporal cortices and a thicker superior parietal lobule and occipital pole compared with the controls. Mean cortical thickness did not differ between the groups. Over time, excessive cortical thinning was found in widespread areas on the cortical mantle, most pronounced bilaterally in the temporal cortex and in the left frontal area. Poor outcome in patients was associated with more pronounced cortical thinning. Higher cumulative intake of typical antipsychotics during the scan interval was associated with more pronounced cortical thinning, whereas higher cumulative intake of atypical antipsychotic medication was associated with less pronounced cortical thinning. CONCLUSIONS: In schizophrenia, the cortex shows excessive thinning over time in widespread areas of the brain, most pronounced in the frontal and temporal areas, and progresses across the entire course of the illness. The excessive thinning of the cortex appears related to outcome and medication intake.

Multivariate analysis of MRI data for Alzheimer's disease, mild cognitive impairment and healthy controls.

We have used multivariate data analysis, more specifically orthogonal partial least squares to latent structures (OPLS) analysis, to discriminate between Alzheimer's disease (AD), mild cognitive impairment (MCI) and elderly control subjects combining both regional and global magnetic resonance imaging (MRI) volumetric measures. In this study, 117 AD patients, 122 MCI patients and 112 control subjects (from the AddNeuroMed study) were included. High-resolution sagittal 3D MP-RAGE datasets were acquired from each subject. Automated regional segmentation and manual outlining of the hippocampus were performed for each image. Altogether this yielded volumes of 24 different anatomically defined structures which were used for OPLS analysis. 17 randomly selected AD patients, 12 randomly selected control subjects and the 22 MCI subjects who converted to AD at 1-year follow up were excluded from the initial OPLS analysis to provide a small external test set for model validation. Comparing AD with controls we found a sensitivity of 87% and a specificity of 90% using hippocampal measures alone. Combining both global and regional measures resulted in a sensitivity of 90% and a specificity of 94%. This increase in sensitivity and specificity resulted in an increase of the positive likelihood ratio from 9 to 15. From the external test set, the model predicted 82% of the AD patients and 83% of the control subjects correctly. Finally, 73% of the MCI subjects which converted to AD at 1 year follow-up were shown to resemble AD patients more closely than controls. This method shows potential for distinguishing between different patient groups. Combining the different MRI measures together resulted in a significantly better classification than using them separately. OPLS also shows potential for predicting conversion from MCI to AD.

Cannabis use and progressive cortical thickness loss in areas rich in CB1 receptors during the first five years of schizophrenia.

Cerebral grey matter volume reductions are progressive in schizophrenia, with larger grey matter volume decreases associated with cannabis use. It is unknown whether this grey matter loss is globally distributed over the entire brain or more pronounced in specific cortical brain regions. Fifty-one patients with recent-onset schizophrenia and 31 matched healthy subjects were included. For all subjects, magnetic resonance imaging scans were obtained at inclusion and at 5-year follow-up. Nineteen patients (ab-)used cannabis but no other illicit drugs; 32 patients and the healthy comparison subjects did not use any drugs during the 5-year follow-up. At follow-up, clinical outcome was measured. To evaluate the local differences in cortical thickness change over five years between the two groups regression analysis was carried out over the cortical surface. At inclusion cortical thickness did not differ between patients and controls and between cannabis-using and non-using patients. Over the follow-up period we found excessive thinning of the right supplementary motor cortex, inferior frontal cortex, superior temporal gyrus, angular gyrus, occipital and parietal lobe in patients relative to controls after controlling for cannabis use. Patients who used cannabis showed additional thinning in the left dorsolateral prefrontal cortex (DLPFC), left anterior cingulate cortex (ACC) and left occipital lobe as compared to those patients that did not use cannabis during the scan interval. First-episode schizophrenia patients who use cannabis show a more pronounced cortical thinning than non-using patients in areas known for their high density of CB1 receptors, such as the ACC and the DLPFC.

Stress regulation in the central nervous system: evidence from structural and functional neuroimaging studies in human populations - 2008 Curt Richter Award Winner.

The metabolic effects of stress are known to have significant health effects in both humans and animals. Most of these effects are mediated by the major stress hormonal axis in the body, the hypothalamic-pituitary-adrenal (HPA) axis. Within the central nervous system (CNS), the hippocampus, the amygdala and the prefrontal cortex as part of the limbic system are believed to play important roles in the regulation of the HPA axis. With the advent of structural and functional neuroimaging techniques, the role of different CNS structures in the regulation of the HPA axis can be investigated more directly. In the current paper, we summarize the findings obtained in our laboratory in the context of stress and HPA axis regulation. Our laboratory has developed and contributed to the development of manual and automated segmentation protocols from structural magnetic resonance imaging (MRI) scans for assessment of hippocampus, amygdala, medial temporal lobe and frontal lobe structures. Employing these protocols, we could show significant age-related changes in HC volumes, which were different between men and women, with pre-menopausal women showing smaller age-related volume decline compared to men. We could recently extent these findings by showing how estrogen therapy after menopause leads to higher volumes in the HC. Investigating possible neurotoxicity effects of steroids, we showed effects of long-term steroid exposure on HC volumes, and investigated variability of HC volumes in relation to HPA axis regulation in young and elderly populations. Here, we were able to follow-up from non-imaging studies showing that subjects low in self-esteem have higher cortisol stress responses, and the HC emerged as the critical link between these variables. Recently, we have made two more important discoveries with regard to HC volume: we could show that HC volume is as variable in young as it is in older adults, in subjects ranging in age from 18 to 80 years. Also, we have linked birth weight and maternal care to HC volumes in young adults, demonstrating the effects of variations in maternal care on the integrity of the CNS. Besides structural assessments, there is increasing interest in functional techniques to investigate possible links between CNS activity and HPA axis regulation. These two approaches complement each other; some aspects of HPA axis regulation might be linked to the integrity of a specific CNS structure, while other aspects might be linked to the function of a specific structure with no involvement of CNS morphology. Thus, we have developed a mental arithmetic stress task that can be employed in functional neuroimaging studies, and have used it in a number of functional neuroimaging studies. Employing positron emission tomography (PET), we were able to demonstrate that stress causes dopamine release if subjects reported low maternal care early in life. Finally, employing the task in functional magnetic resonance imaging (fMRI), we could show how exposure to stress and activation of the HPA axis are associated with decreased activity in major portions of the limbic system, a result that allows to speculate on the effects of stress on cognitive and emotional regulation in the brain. Taken together, the use of neuroimaging techniques in Psychoneuroendocrinology opens exciting new possibilities for the investigation of stress effects in the central nervous system.

A new improved version of the realistic digital brain phantom.

Image analysis methods must be tested and evaluated within a controlled environment. Simulations can be an extremely helpful tool for validation because ground truth is known. We created the digital brain phantom that is at the heart of our publicly available database of realistic simulated magnetic resonance image (MRI) volumes known as BrainWeb. Even though the digital phantom had l mm(3) isotropic voxel size and a small number of tissue classes, the BrainWeb database has been used in more than one hundred peer-reviewed publications validating different image processing methods. In this paper, we describe the next step in the natural evolution of BrainWeb: the creation of digital brain phantom II that includes three major improvements over the original phantom. First, the realism of the phantom, and the resulting simulations, was improved by modeling more tissue classes to include blood vessels, bone marrow and dura mater classes. In addition. a more realistic skull class was created. The latter is particularly useful for SPECT, PET and CT simulations for which bone attenuation has an important effect. Second, the phantom was improved by an eight-fold reduction in voxel volume to 0.125 mm(3). Third, the method used to create the new phantom was modified not only to take into account the segmentation of these new structures, but also to take advantage of many more automated procedures now available. The overall process has reduced subjectivity and manual intervention when compared to the original phantom, and the process may be easily applied to create phantoms from other subjects. MRI simulations are shown to illustrate the difference between the previous and the new improved digital brain phantom II. Example PET and SPECT simulations are also presented.

A review of calibration techniques for freehand 3-D ultrasound systems.

Three-dimensional (3-D) ultrasound (US) is an emerging new technology with numerous clinical applications. Ultrasound probe calibration is an obligatory step to build 3-D volumes from 2-D images acquired in a freehand US system. The role of calibration is to find the mathematical transformation that converts the 2-D coordinates of pixels in the US image into 3-D coordinates in the frame of reference of a position sensor attached to the US probe. This article is a comprehensive review of what has been published in the field of US probe calibration for 3-D US. The article covers the topics of tracking technologies, US image acquisition, phantom design, speed of sound issues, feature extraction, least-squares minimization, temporal calibration, calibration evaluation techniques and phantom comparisons. The calibration phantoms and methods have also been classified in tables to give a better overview of the existing methods.