Spinal Cord Sarcoidosis Occurring at Sites of Spondylotic Stenosis, Mimicking Spondylotic Myelopathy: A Case Series and Review of the Literature.

Sarcoidosis is a multisystem granulomatous disease, with intramedullary spinal cord involvement seen in <1% of cases. This case series illustrates the clinical presentations and imaging findings of 5 patients with intramedullary spinal neurosarcoidosis occurring at sites of spondylotic spinal canal stenosis, which can be indistinguishable from spondylotic myelopathy with cord enhancement. Both entities are most common in middle-aged men and present with weeks to months of motor and sensory symptoms. On imaging, both can have focal spinal cord enhancement and longitudinally extensive signal abnormality centered at or just below the level of spinal canal stenosis. On the basis of our experience, we suggest that in patients with cord enhancement centered at or just below a site of spinal canal stenosis, consideration should be given to chest imaging and lymph node biopsy when applicable, to assess for the possibility of underlying sarcoidosis before surgical decompression.

Neuroaxial Infantile Hemangiomas: Imaging Manifestations and Association with Hemangioma Syndromes.

BACKGROUND AND PURPOSE: Infantile hemangiomas are common lesions in the pediatric population; in rare cases, an infantile hemangioma can be detected along the neural axis. The purposes of our study included determination of the incidence, location, and imaging appearance of neuroaxial infantile hemangiomas and their syndromic association. We also assessed additional features of cerebral and cardiovascular anomalies that may be associated with neuroaxial lesions. MATERIALS AND METHODS: A retrospective cohort study was performed, searching the radiology database for patients with segmental infantile hemangiomas referred for assessment of possible hemangioma syndromes. We retrospectively reviewed brain and spine MR imaging studies, with particular attention paid to neuroaxial vascular lesions, as well as the relevant clinical data. Neuroaxial hemangioma imaging findings were described, and comparison of segmental cutaneous infantile hemangioma location with the imaging findings was performed in patients with confirmed hemangioma syndromes and in patients with isolated skin infantile hemangioma. RESULTS: Ninety-five patients with segmental infantile hemangioma were included in the study, 42 of whom had a hemangioma syndrome; of those, 41 had posterior fossa brain malformations, hemangioma, arterial lesions, cardiac abnormalities, and eye abnormalities (PHACE) syndrome and 1 had diffuse neonatal hemangiomatosis. Neuroaxial involvement was detected in 20/42 patients (48%) with hemangioma syndromes and in no subjects with isolated segmental infantile hemangioma (P < .001). The most common intracranial hemangioma location was within the ipsilateral internal auditory canal (83%). CONCLUSIONS: Many pediatric patients with segmental infantile hemangioma in the setting of hemangioma syndromes, especially those with PHACE, had neuroaxial hemangiomas. This finding may potentially lead to requiring additional clinical evaluation and management of these patients.

Am I Ready to Be an Independent Neuroradiologist? Objective Trends in Neuroradiology Fellows' Performance during the Fellowship Year.

BACKGROUND AND PURPOSE: Aside from basic Accreditation Council for Graduate Medical Education guidelines, few metrics are in place to monitor fellows' progress. The purpose of this study was to determine objective trends in neuroradiology fellowship training on-call performance during an academic year. MATERIALS AND METHODS: We retrospectively reviewed the number of cross-sectional neuroimaging studies dictated with complete reports by neuroradiology fellows during independent call. Monthly trends in total call cases, report turnaround times, relationships between volume and report turnaround times, and words addended to preliminary reports by attending neuroradiologists were evaluated with regression models. Monthly variation in frequencies of call-discrepancy macros were assessed via χ2 tests. Changes in frequencies of specific macro use between fellowship semesters were assessed via serial 2-sample tests of proportions. RESULTS: From 2012 to 2017, for 29 fellows, monthly median report turnaround times significantly decreased during the academic year: July (first month) = 79 minutes (95% CI, 71-86 minutes) and June (12th month) = 55 minutes (95% CI, 52-60 minutes; P value = .023). Monthly report turnaround times were inversely correlated with total volumes for CT (r = -0.70, F = 9.639, P value = .011) but not MR imaging. Words addended to preliminary reports, a surrogate measurement of report clarity, slightly improved and discrepancy rates decreased during the last 6 months of fellowship. A nadir for report turnaround times, discrepancy errors, and words addended to reports was seen in December and January. CONCLUSIONS: Progress through fellowship correlates with a decline in report turnaround times and discrepancy rates for cross-sectional neuroimaging call studies and slight improvement in indirect quantitative measurement of report clarity. These metrics can be tracked throughout the academic year, and the midyear would be a logical time point for programs to assess objective progress of fellows and address any deficiencies.

Reversible Dilation of the Superior Ophthalmic Vein in Intubated Patients.

BACKGROUND AND PURPOSE: Superior ophthalmic vein enlargement has typically been associated with increased intracranial or orbital pressure. This study evaluates the incidence of superior ophthalmic vein enlargement in intubated patients without pre-existing intracranial or intraorbital pathologies. MATERIALS AND METHODS: Two cohorts (patients with trauma and epilepsy patients undergoing stereotactic intracranial lead placement) who underwent CT while intubated and shortly following extubation and a cohort of 30 outpatients with a history of headache and normal head CT findings (healthy controls) were included. The superior ophthalmic vein diameter was measured on all scans. RESULTS: Seventy patients intubated for trauma and 45 patients with intraoperative CT were included (n = 115). While intubated, 66% of the total sample had at least unilateral superior ophthalmic vein dilation of >2.5 mm and 48% had bilateral dilation. Fifty-seven percent of patients with trauma and 84% of intraoperative patients with dilated superior ophthalmic veins showed reversal of mean superior ophthalmic vein dilation to <2.5 mm on postextubation CT. The mean superior ophthalmic vein diameter decreased an average of 1.2 mm following extubation. Changes in superior ophthalmic vein diameter between intubated and extubated states were statistically significant (P < .001). Differences between the control group and the extubated subjects were not statistically significant (P = .21). CONCLUSIONS: Bilateral dilation of the superior ophthalmic vein is common in intubated patients and usually reverses following extubation. In the appropriate clinical setting, this knowledge will prevent misinterpretation of prominent superior ophthalmic veins as automatically indicative of an underlying pathology.

Using Body Mass Index to Predict Needle Length in Fluoroscopy-Guided Lumbar Punctures.

BACKGROUND AND PURPOSE: Predicting the appropriate needle length to use in oblique interlaminar-approach fluoroscopy-guided lumbar punctures in patients with a large body mass index is difficult. Using the wrong needle length can lead to an increased radiation dose and patient discomfort. We hypothesized that body mass index could help determine the appropriate needle length to use in patients. MATERIALS AND METHODS: We randomly selected patients who underwent oblique interlaminar-approach fluoroscopy-guided lumbar punctures and had cross-sectional imaging of the lumbar spine within 1 year of imaging (n = 50). The distance from the skin to the midlumbar spinal canal (skin-canal distance) at the level of the lumbar puncture was measured by using an oblique angle of 8.6°, which is an average of angles most often used to perform the procedure. A formula was devised using the skin-canal distance and body mass index to predict the appropriate needle length, subsequently confirmed in 45 patients. RESULTS: The body mass index and skin-canal distance were significantly higher (P < .001) in patients who underwent fluoroscopy-guided lumbar puncture with 5- or 7-inch needles (n = 22) than in patients requiring 3.5-inch needles (n = 28). Using linear regression, we determined the formula to predict the needle length as Skin-Canal Distance (inches) = 0.077 × Body Mass Index + 0.88. We found a strong correlation (P < .001) between the predicted and actual skin canal distance in 45 patients, and our formula better predicted the skin-canal distance than others. CONCLUSIONS: We designed a formula that uses body mass index to predict the appropriate needle length in oblique interlaminar-approach fluoroscopy-guided lumbar punctures and validated it by demonstrating a strong correlation between the predicted and actual skin-canal distance.

Use of Standardized Uptake Value Ratios Decreases Interreader Variability of [18F] Florbetapir PET Brain Scan Interpretation.

BACKGROUND AND PURPOSE: Fluorine-18 florbetapir is a recently developed ß-amyloid plaque positron-emission tomography imaging agent with high sensitivity, specificity, and accuracy in the detection of moderate-to-frequent cerebral cortical ß-amyloid plaque. However, the FDA has expressed concerns about the consistency of interpretation of [(18)F] florbetapir PET brain scans. We hypothesized that incorporating automated cerebral-to-whole-cerebellar standardized uptake value ratios into [(18)F] florbetapir PET brain scan interpretation would reduce this interreader variability. MATERIALS AND METHODS: This randomized, blinded-reader study used previously acquired [(18)F] florbetapir scans from 30 anonymized patients who were enrolled in the Alzheimer's Disease Neuroimaging Initiative 2. In 4 separate, blinded-reading sessions, 5 readers classified 30 cases as positive or negative for significant ß-amyloid deposition either qualitatively alone or qualitatively with additional adjunct software that determined standardized uptake value ratios. A κ coefficient was used to calculate interreader agreement with and without the use of standardized uptake value ratios. RESULTS: There was complete interreader agreement on 20/30 cases of [(18)F] florbetapir PET brain scans by using qualitative interpretation and on 27/30 scans interpreted with the adjunct use of standardized uptake value ratios. The κ coefficient for the studies read with standardized uptake value ratios (0.92) was significantly higher compared with the qualitatively read studies (0.69, P = .006). CONCLUSIONS: Use of standardized uptake value ratios improves interreader agreement in the interpretation of [(18)F] florbetapir images.

Incidental radiologic findings in the 22q11.2 deletion syndrome.

BACKGROUND AND PURPOSE: The 22q11.2 deletion syndrome is a common genetic microdeletion syndrome that results in cognitive delays and an increased risk of several psychiatric disorders, particularly schizophrenia. The current study investigates the prevalence of incidental neuroradiologic findings within this population and their relationships with psychiatric conditions. MATERIALS AND METHODS: Brain MR imaging from 58 individuals with 22q11.2 deletion syndrome was reviewed by board-certified radiologists by using standard clinical procedures. Intracranial incidental findings were classified into 8 categories and compared with a large typically developing cohort. RESULTS: The rate of incidental findings was significantly higher (P < .0001) in 22q11.2 deletion syndrome compared with typically developing individuals, driven by a high prevalence of cavum septum pellucidum (19.0%) and white matter abnormalities (10.3%). Both of these findings were associated with psychosis in 22q11.2 deletion syndrome. CONCLUSIONS: Cavum septum pellucidum and white matter hyperintensities are significantly more prevalent in patients with the 22q11.2 deletion syndrome and may represent biomarkers for psychosis.

Are there differences in brain morphometry between twins and unrelated singletons? A pediatric MRI study.

Twins provide a unique capacity to explore relative genetic and environmental contributions to brain development, but results are applicable to non-twin populations only to the extent that twin and singleton brains are alike. A reason to suspect differences is that as a group twins are more likely than singletons to experience adverse prenatal and perinatal events that may affect brain development. We sought to assess whether this increased risk leads to differences in child or adolescent brain anatomy in twins who do not experience behavioral or neurological sequelae during the perinatal period. Brain MRI scans of 185 healthy pediatric twins (mean age = 11.0, SD = 3.6) were compared to scans of 167 age- and sex-matched unrelated singletons on brain structures measured, which included gray and white matter lobar volumes, ventricular volume, and area of the corpus callosum. There were no significant differences between groups for any structure, despite sufficient power for low type II (i.e. false negative) error. The implications of these results are twofold: (1) within this age range and for these measures, it is appropriate to include healthy twins in studies of typical brain development, and (2) findings regarding heritability of brain structures obtained from twin studies can be generalized to non-twin populations.

Identification of genetically mediated cortical networks: a multivariate study of pediatric twins and siblings.

Structural magnetic resonance imaging data from 308 twins, 64 singleton siblings of twins, and 228 singletons were analyzed using structural equation modeling and selected multivariate methods to identify genetically mediated intracortical associations. Principal components analyses (PCA) of the genetic correlation matrix indicated a single factor accounting for over 60% of the genetic variability in cortical thickness. When covaried for mean global cortical thickness, PCA, cluster analyses, and graph models identified genetically mediated fronto-parietal and occipital networks. Graph theoretical models suggest that the observed genetically mediated relationships follow small world architectural rules. These findings are largely concordant with other multivariate studies of brain structure and function, the twin literature, and current understanding on the role of genes in cortical neurodevelopment.

Dorsal forebrain anomaly in Williams syndrome.

BACKGROUND: Williams syndrome (WMS) is a rare neurogenetic condition with a behavioral phenotype that suggests a dorsal and/or ventral developmental dissociation, with deficits in dorsal but not the ventral hemispheric visual stream. A shortened extent of the dorsal central sulcus has been observed in autopsy specimens. OBJECTIVE: To compare gross anatomical features between the dorsal and ventral portions of the cerebral hemispheres by examining the dorsal extent of the central sulcus in brain magnetic resonance images from a sample of subjects with WMS and age- and sex-matched control subjects. SUBJECTS: Twenty-one subjects having clinically and genetically diagnosed WMS (mean +/- SD age, 28.9 +/- 7.9 years) were compared with 21 age- and sex-matched typically developing controls (mean +/- SD age, 28.8 +/- 7.9 years). DESIGN: High-resolution structural magnetic resonance images were acquired. The extent of the central sulcus was qualitatively assessed via surface projections of the cerebral cortex. RESULTS: The dorsal central sulcus is less likely to reach the interhemispheric fissure in subjects with WMS than in controls for both left (P< .001, chi(2) = 15.79) and right (P< .001, chi(2) = 12.95) hemispheres. No differences between the groups were found in the ventral extent of the central sulcus. CONCLUSIONS: Anomalies in the dorsal region in patients with WMS are indicative of early neurodevelopmental problems affecting the development of the dorsal forebrain and are most likely related to the deficits in visuospatial ability and behavioral timing often observed in this condition.

Enlarged cerebellar vermis in Williams syndrome.

Williams syndrome (WMS) is a rare genetic disorder characterized by relative preservations of language ability and facial processing despite deficits in overall intelligence, problem solving, and visuospatial processing. Subjects with WMS also display hypersocial behavior and excessive linguistic affect during conversations and when giving narratives. Neuroimaging studies have shown global reductions in the brain volumes of subjects with WMS compared with normal controls, but with preservations in cerebellar volume. This study examines the neuroanatomic structure of the cerebellar vermis in 20 subjects with WMS and 20 age- and gender-matched controls via high-resolution magnetic resonance imaging. The vermis was divided into lobules I-V, VI-VII, and VIII-X. Lobules VI-VII and VIII-X were both relatively enlarged in the WMS group, and after adjusting for the smaller size of the WMS brain, the posterior vermis was significantly larger in WMS (Mann-Whitney z-value=4.27; P<0.001). Given that reductions in posterior vermis size have been implicated in flattened affect and autistic features, increased vermis size in subjects with WMS may be related to the hypersociality and heightened affective expression characteristic of individuals with this genetic condition.

Neuroanatomy of Down's syndrome: a high-resolution MRI study.

OBJECTIVE: Down's syndrome, the most common genetic cause of mental retardation, results in characteristic physical and neuropsychological findings, including mental retardation and deficits in language and memory. This study was undertaken to confirm previously reported abnormalities of regional brain volumes in Down's syndrome by using high-resolution magnetic resonance imaging (MRI), determine whether these volumetric abnormalities are present from childhood, and consider the relationship between neuroanatomic abnormalities and the cognitive profile of Down's syndrome. METHOD: Sixteen children and young adults with Down's syndrome (age range=5-23 years) were matched for age and gender with 15 normal comparison subjects. High-resolution MRI scans were quantitatively analyzed for measures of overall and regional brain volumes and by tissue composition. RESULTS: Consistent with prior imaging studies, subjects with Down's syndrome had smaller overall brain volumes, with disproportionately smaller cerebellar volumes and relatively larger subcortical gray matter volumes. Also noted was relative preservation of parietal lobe gray and temporal lobe white matter in subjects with Down's syndrome versus comparison subjects. No abnormalities in pattern of brain asymmetry were noted in Down's syndrome subjects. CONCLUSIONS: The results largely confirm findings of previous studies with respect to overall patterns of brain volumes in Down's syndrome and also provide new evidence for abnormal volumes of specific regional tissue components. The presence of these abnormalities from an early age suggests that fetal or early postnatal developmental differences may underlie the observed pattern of neuroanatomic abnormalities and contribute to the specific cognitive and developmental deficits seen in individuals with Down's syndrome.

Functional brain imaging study of mathematical reasoning abilities in velocardiofacial syndrome (del22q11.2).

PURPOSE: Children with velocardiofacial syndrome (VCFS) often have deficits in mathematical reasoning. Previous research has suggested that structural abnormalities in the parietal lobe region might underlie these deficits. The present study utilized functional magnetic resonance imaging (fMRI) to explore the relationship between brain function and mathematical performance in VCFS. METHODS: Eight children with VCFS and eight comparison subjects underwent fMRI scanning and completed an arithmetic computation task. RESULTS: In the VCFS group, increased activation was observed in the left supramarginal gyrus (LSMG) as the task difficulty increased. CONCLUSION: Aberrant LSMG activation, possibly due to structural deficits of the left parietal lobe, may explain decrements in arithmetic performance observed in VCFS.

Amygdala and hippocampal volumes in children with Down syndrome: a high-resolution MRI study.

The objective of this study was to use high-resolution MRI techniques to determine whether children with Down syndrome exhibit decreases in hippocampal and amygdala volumes similar to those demonstrated in recent studies of adults with this condition. When corrected for overall brain volumes, amygdala volumes did not differ between groups but hippocampal volumes were significantly smaller in the Down syndrome group. These findings suggest that the hippocampal volume reduction seen in adults with Down syndrome may be primarily due to early developmental differences rather than neurodegenerative changes.

Corpus callosum morphology of Williams syndrome: relation to genetics and behavior.

As the largest interhemispheric commissure in the brain, the corpus callosum is of particular interest in disorders that may preferentially affect white matter development such as Williams syndrome (WS). Individuals with WS possess a remarkable array of neurobehavioral peaks and valleys, including deficits in visuospatial ability, mathematics, and attention, but with relative preservation of language and affect. Our study measured the corpus callosum and its primary subdivisions using high-resolution MRI in 20 individuals with WS (13 females and seven males; mean age 28.5, SD 8.3 years; range 19 to 44 years) and 20 age- and sex-matched control participants (mean age 28.5, SD 8.2 years; range 19 to 48 years). Total midsagittal corpus callosum area was reduced (F=4.5, p=0.04, df=36) in the WS population. The area of the splenium (F=12.4, p=0.001, df=36) and isthmus (F=9.4, p=0.004, df=36) were disproportionately reduced in WS beyond the absolute reduction of the entire corpus callosum. These reductions are in concordance with other neuroanatomical findings of decreased parietooccipital volumes as well as the observed visuospatial problems associated with WS.

A quantitative MRI study of posterior fossa development in velocardiofacial syndrome.

BACKGROUND: Velocardiofacial syndrome (VCFS) has been identified as a risk factor for developing schizophrenia. Qualitative neuroimaging studies indicated that VCFS was frequently associated with abnormal development of structures in the posterior fossa of the brain. The objective of this investigation was to identify the specific structures affected in the posterior fossa and investigate the association of these neuroanatomic variations with behaviors potentially related to later-onset psychiatric disorders. METHODS: Twenty-four children and adolescents with VCFS individually matched for age and gender with 24 control subjects received magnetic resonance imaging scans. Analysis of covariance models were used to investigate regional brain differences. Association between brain areas and behaviors measured on the Child Behavior Checklist (CBCL) were assessed using simple regression models. RESULTS: Children with VCFS had significantly smaller size of vermal lobules VI--VII and the pons after adjusting for overall brain size. There were no significant associations between scores on the CBCL and measures of neuroanatomic variation within the VCFS group. CONCLUSIONS: Structural alterations of the posterior fossa in VCFS are specifically limited to cerebellar vermis lobules VI--VII and pons. Previous literature has suggested that the vermis is involved in social cognition, and alteration of lobules VI--VII could therefore partially explain the neurobehavioral profile associated with VCFS.

Analysis of cerebral shape in Williams syndrome.

BACKGROUND: As a neurobehavioral disorder with a specific neurocognitive profile and a well-defined genetic etiology, Williams syndrome (WMS) provides an exceptional opportunity to examine associations among measures of behavior, neuroanatomy, and genetics. This study was designed to determine how cerebral shape differs between the brains of subjects with WMS and those of normal controls. SUBJECTS: Twenty adults with clinically and genetically diagnosed WMS (mean +/- SD age, 28.5 +/- 8.3 years) and 20 healthy, age- and sex-matched controls (mean +/- SD age, 28.5 +/- 8.2 years). DESIGN: High-resolution structural magnetic resonance imaging data were used for shape-based morphological analysis of the right and left cerebral hemispheres and the corpus callosum. Statistical analyses were performed to examine group differences. RESULTS: Both right and left cerebral hemispheres of subjects with WMS bend to a lesser degree in the sagittal plane than normal controls (P<.001). The corpus callosum also bends less in subjects with WMS (P =.05). In addition, subjects with WMS have decreased cerebral (P<.001) and corpus callosum (P<.001) midline lengths. CONCLUSIONS: Subjects with WMS have significantly different cerebral shape from normal controls, perhaps due to decreased parieto-occipital lobe volumes relative to frontal regions. The similar observation in the corpus callosum may be associated with a decreased size of the splenium in WMS. These findings may provide important clues to the effect of genes in the WMS-deleted region on brain development.

Brain imaging in neurogenetic conditions: realizing the potential of behavioral neurogenetics research.

Behavioral neurogenetics research is a new method of scientific inquiry that focuses on investigation of neurodevelopmental dysfunction associated with specific genetic conditions. This research method provides a powerful tool for scientific inquiry into human gene-brain-behavior linkages that complements more traditional research approaches. In particular, the use of specific genetic conditions as models of common behavioral and cognitive disorders occurring in the general population can reveal insights into neurodevelopmental pathways that might otherwise be obscured or diluted when investigating more heterogeneous, behaviorally defined subject groups. In this paper, we review five genetic conditions that commonly give rise to identifiable neurodevelopmental and neuropsychiatric disability in children: fragile X syndrome, velo-cardio-facial syndrome, Williams syndrome, Turner syndrome, and Klinefelter syndrome. While emphasis is placed on describing the brain morphology associated with these conditions as revealed by neuroimaging studies, we also include information pertaining to molecular genetic, postmortem, and neurobehavioral investigations to illustrate how behavioral neurogenetics research can contribute to an improved understanding of brain disorders in childhood.

Morphological alteration of temporal lobe gray matter in dyslexia: an MRI study.

Functional imaging studies of developmental dyslexia have reported reduced task-related neural activity in the temporal and inferior parietal cortices. To examine the possible contribution of subtle anatomic deviations to these reductions, volumes were measured for the major lobes of the brain, the subcortical nuclei, cerebellum, and lateral ventricles on magnetic resonance imaging (MRI) scans from 16 right-handed dyslexic men, ages 18 to 40, and 14 matched controls, most of whom had previously undergone PET imaging. A specific decrease in tissue volume was localized to the temporal lobes and was particularly prominent on the left (p < .01). An analysis of tissue composition revealed that this reduction was primarily attributable to decreased gray matter within the left temporal lobe (p < .002). Further segmentation of the temporal lobe showed that this reduction was not confined to the superior temporal gyrus, the primary location of primary auditory cortex. Reductions of temporal lobe gray matter may reflect a regional decrease in neuronal number or neuropil, which in turn may result in reading impairment.

IV. Neuroanatomy of Williams syndrome: a high-resolution MRI study.

Williams syndrome (WMS), a genetic condition resulting from a contiguous deletion on the long arm of chromosome 7, is associated with a relatively consistent profile of neurocognitive and neurobehavioral features. The distinctiveness and regularity of the profile of learning and behavioral characteristics in this genetic condition suggests that underlying neurobiological correlates may be identifiable. In this initial study, we report findings derived from a high-resolution neuroimaging study of 14 young adult subjects with WMS and an individually matched normal control group. Compared to controls, subjects with WMS were noted to have decreased overall brain and cerebral volumes, relative preservation of cerebellar and superior temporal gyrus (STG) volumes, and disproportionate volume reduction of the brainstem. Analyses also suggested that the pattern of cerebral lobe proportions in WMS may be altered compared to normal controls with a greater ratio of frontal to posterior (parietal+occipital) tissue. Assessment of tissue composition indicated that, relative to controls, individuals with WMS have relative preservation of cerebral gray matter volume and disproportionate reduction in cerebral white matter volume. However, within the cerebral gray matter tissue compartment, the right occipital lobe was noted to have excess volume loss. Combined with our growing knowledge of the function of genes in the commonly deleted region for WMS, more detailed information regarding the structure and function of the WMS brain will provide a unique opportunity for elucidating meaningful correlations amongst genetic, neurobiological, and neurobehavioral factors in humans.