Xuejun Hao

Brain anomalies in children exposed prenatally to a common organophosphate pesticide

Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9–11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure × IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose–response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain.

Cortical thinning in persons at increased familial risk for major depression

The brain disturbances that place a person at risk for developing depression are unknown. We imaged the brains of 131 individuals, ages 6 to 54 years, who were biological descendants (children or grandchildren) of individuals identified as having either moderate to severe, recurrent, and functionally debilitating depression or as having no lifetime history of depression. We compared cortical thickness across high- and low-risk groups, detecting large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere in persons at high risk. Thinning correlated with measures of current symptom severity, inattention, and visual memory for social and emotional stimuli. Mediator analyses indicated that cortical thickness mediated the associations of familial risk with inattention, visual memory, and clinical symptoms. These findings suggest that cortical thinning in the right hemisphere produces disturbances in arousal, attention, and memory for social stimuli, which in turn may increase the risk of developing depressive illness.

Anatomical Brain Images Alone Can Accurately Diagnose Chronic Neuropsychiatric Illnesses

Objective Diagnoses using imaging-based measures alone offer the hope of improving the accuracy of clinical diagnosis, thereby reducing the costs associated with incorrect treatments. Previous attempts to use brain imaging for diagnosis, however, have had only limited success in diagnosing patients who are independent of the samples used to derive the diagnostic algorithms. We aimed to develop a classification algorithm that can accurately diagnose chronic, well-characterized neuropsychiatric illness in single individuals, given the availability of sufficiently precise delineations of brain regions across several neural systems in anatomical MR images of the brain. Methods We have developed an automated method to diagnose individuals as having one of various neuropsychiatric illnesses using only anatomical MRI scans. The method employs a semi-supervised learning algorithm that discovers natural groupings of brains based on the spatial patterns of variation in the morphology of the cerebral cortex and other brain regions. We used split-half and leave-one-out cross-validation analyses in large MRI datasets to assess the reproducibility and diagnostic accuracy of those groupings. Results In MRI datasets from persons with Attention-Deficit/Hyperactivity Disorder, Schizophrenia, Tourette Syndrome, Bipolar Disorder, or persons at high or low familial risk for Major Depressive Disorder, our method discriminated with high specificity and nearly perfect sensitivity the brains of persons who had one specific neuropsychiatric disorder from the brains of healthy participants and the brains of persons who had a different neuropsychiatric disorder. Conclusions Although the classification algorithm presupposes the availability of precisely delineated brain regions, our findings suggest that patterns of morphological variation across brain surfaces, extracted from MRI scans alone, can successfully diagnose the presence of chronic neuropsychiatric disorders. Extensions of these methods are likely to provide biomarkers that will aid in identifying biological subtypes of those disorders, predicting disease course, and individualizing treatments for a wide range of neuropsychiatric illnesses.

Morphological Abnormalities of the Thalamus in Youths With Attention Deficit Hyperactivity Disorder

OBJECTIVE The role of the thalamus in the genesis of attention deficit hyperactivity disorder (ADHD) remains poorly understood. The authors used anatomical MRI to examine the morphology of the thalamus in youths with ADHD and healthy comparison youths. METHOD The authors examined 46 youths with ADHD and 59 comparison youths 8-18 years of age in a cross-sectional case-control study. Conventional volumes and measures of surface morphology of the thalamus served as the main outcome measures. RESULTS A mixed-effects model comparing whole thalamic volumes revealed no significant differences between groups. Maps of the thalamic surface revealed significantly smaller regional volumes bilaterally in the pulvinar in youths with ADHD relative to comparison subjects. Post hoc analyses showed that ADHD patients who received stimulants (N=31) had larger conventional thalamic volumes than untreated youths with ADHD, and maps of the thalamic surface showed enlargement over the pulvinar in those receiving stimulants. Smaller regional volumes in the right lateral and left posterior thalamic surfaces were associated with more severe hyperactivity symptoms, whereas larger regional volumes in the right medial thalamic surfaces were associated with more severe symptoms of inattention. CONCLUSION These findings demonstrate reduced pulvinar volumes in youths with ADHD and indicate that this same area is relatively enlarged in patients treated with stimulants compared to those untreated. Associations of hyperactivity scores with smaller regional volumes on the lateral thalamic surface and inattention scores with larger regional volumes on the medial thalamic surface suggest the differential involvement of thalamic subcircuits in the pathogenesis of differing ADHD symptoms.

Effects of prenatal exposure to air pollutants (polycyclic aromatic hydrocarbons) on the development of brain white matter, cognition, and behavior in later childhood.

IMPORTANCE Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous and neurotoxic environmental contaminants. Prenatal PAH exposure is associated with subsequent cognitive and behavioral disturbances in childhood. OBJECTIVES To identify the effects of prenatal PAH exposure on brain structure and to assess the cognitive and behavioral correlates of those abnormalities in school-age children. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional imaging study in a representative community-based cohort followed up prospectively from the fetal period to ages 7 to 9 years. The setting was urban community residences and an academic imaging center. Participants included a sample of 40 minority urban youth born to Latina (Dominican) or African American women. They were recruited between February 2, 1998, and March 17, 2006. MAIN OUTCOMES AND MEASURES Morphological measures that index local volumes of the surface of the brain and of the white matter surface after cortical gray matter was removed. RESULTS We detected a dose-response relationship between increased prenatal PAH exposure (measured in the third trimester but thought to index exposure for all of gestation) and reductions of the white matter surface in later childhood that were confined almost exclusively to the left hemisphere of the brain and that involved almost its entire surface. Reduced left hemisphere white matter was associated with slower information processing speed during intelligence testing and with more severe externalizing behavioral problems, including attention-deficit/hyperactivity disorder symptoms and conduct disorder problems. The magnitude of left hemisphere white matter disturbances mediated the significant association of PAH exposure with slower processing speed. In addition, measures of postnatal PAH exposure correlated with white matter surface measures in dorsal prefrontal regions bilaterally when controlling for prenatal PAH. CONCLUSIONS AND RELEVANCE Our findings suggest that prenatal exposure to PAH air pollutants contributes to slower processing speed, attention-deficit/hyperactivity disorder symptoms, and externalizing problems in urban youth by disrupting the development of left hemisphere white matter, whereas postnatal PAH exposure contributes to additional disturbances in the development of white matter in dorsal prefrontal regions.

MRI hippocampal and entorhinal cortex mapping in predicting conversion to Alzheimer's disease ☆

OBJECTIVE Using MRI surface morphometry mapping, to evaluate local deformations of the hippocampus, parahippocampal gyrus, and entorhinal cortex in predicting conversion from mild cognitive impairment (MCI) to Alzheimers disease (AD). METHODS Baseline brain MRI with surface morphological analysis was performed in 130 outpatients with MCI, broadly defined, and 61 healthy controls followed for an average of 4 years in a single site study. RESULTS Patients with MCI differed from controls in several regions of the hippocampus and entorhinal cortex, and to a lesser extent in the parahippocampal gyrus. In the MCI sample, Cox regression models were conducted for time to conversion comparing converters to AD (n=31) and non-converters (n=99), controlling for age, sex and education. Converters showed greater atrophy in the head of the hippocampus, predominantly in the CA1 region and subiculum, and in the entorhinal cortex, especially in the anterior-inferior pole bilaterally. When distances of specific points representing localized inward deformation were entered together with the corresponding hippocampal or entorhinal cortex volume in the same Cox regression model, the distances remained highly significant whereas the volumes of the corresponding structures were either marginally significant or not significant. Inclusion of cognitive or memory measures or apolipoprotein E ε4 genotype as covariates, or restricting the sample to patients with amnestic MCI (24 converters and 81 non-converters) did not materially change the findings. In the 3-year follow-up sample of patients with MCI, logistic regression analyses using the same measures and covariates yielded similar results. INTERPRETATION These findings indicate selective early involvement of the CA1 and subiculum regions of the hippocampus and provide new information on early anterior pole involvement in the entorhinal cortex in incipient AD. Fine-grained surface morphometry of medial temporal lobe structures may be superior to volumetric assessment in predicting conversion to AD in patients clinically diagnosed with MCI.

Basal Ganglia Surface Morphology and the Effects of Stimulant Medications in Youth with Attention-Deficit/Hyperactivity Disorder

OBJECTIVE Disturbances in the basal ganglia portions of cortico-striato-thalamo-cortical circuits likely contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The authors examined the morphologic features of the basal ganglia nuclei (caudate, putamen, and globus pallidus) in children with ADHD. METHOD A total of 104 individuals (combined-type ADHD patients: N=47; healthy comparison subjects: N=57), aged 7 to 18 years, were examined in a cross-sectional case-control study using anatomical magnetic resonance imaging. Conventional volumes and the surface morphology for the basal ganglia were measured. RESULTS Overall volumes were significantly smaller only in the putamen. Analysis of the morphological surfaces revealed significant inward deformations in each of the three nuclei, localized primarily in portions of these nuclei that are components of limbic, associative, and sensorimotor pathways in the cortico-striato-thalamo-cortical circuits in which these nuclei reside. The more prominent these inward deformations were in the patient group, the more severe the ADHD symptoms. Surface analyses also demonstrated significant outward deformations of all basal ganglia nuclei in the ADHD children treated with stimulants compared with those ADHD youth who were untreated. These stimulant-associated enlargements were in locations similar to the reduced volumes detected in the ADHD group relative to the comparison group. The outward deformations associated with stimulant medications attenuated the statistical effects of the primary group comparisons. CONCLUSIONS These findings potentially represent evidence of anatomical dysregulation in the circuitry of the basal ganglia in children with ADHD and suggest that stimulants may normalize morphological features of the basal ganglia in children with the disorder.

Neuroanatomical Correlates of Religiosity and Spirituality: A Study in Adults at High and Low Familial Risk for Depression

IMPORTANCE We previously reported a 90% decreased risk in major depression, assessed prospectively, in adult offspring of depressed probands who reported that religion or spirituality was highly important to them. Frequency of church attendance was not significantly related to depression risk. Our previous brain imaging findings in adult offspring in these high-risk families also revealed large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere. OBJECTIVE To determine whether high-risk adults who reported high importance of religion or spirituality had thicker cortices than those who reported moderate or low importance of religion or spirituality and whether this effect varied by family risk status. DESIGN, SETTING, AND PARTICIPANTS Longitudinal, retrospective cohort, familial study of 103 adults (aged 18-54 years) who were the second- or third-generation offspring of depressed (high familial risk) or nondepressed (low familiar risk) probands (first generation). Religious or spiritual importance and church attendance were assessed at 2 time points during 5 years, and cortical thickness was measured on anatomical images of the brain acquired with magnetic resonance imaging at the second time point. MAIN OUTCOMES AND MEASURES Cortical thickness in the parietal regions by risk status. RESULTS Importance of religion or spirituality, but not frequency of attendance, was associated with thicker cortices in the left and right parietal and occipital regions, the mesial frontal lobe of the right hemisphere, and the cuneus and precuneus in the left hemisphere, independent of familial risk. In addition, the effects of importance on cortical thickness were significantly stronger in the high-risk than in the low-risk group, particularly along the mesial wall of the left hemisphere, in the same region where we previously reported a significant thinner cortex associated with a familial risk of developing depressive illness. We note that these findings are correlational and therefore do not prove a causal association between importance and cortical thickness. CONCLUSIONS AND RELEVANCE A thicker cortex associated with a high importance of religion or spirituality may confer resilience to the development of depressive illness in individuals at high familial risk for major depression, possibly by expanding a cortical reserve that counters to some extent the vulnerability that cortical thinning poses for developing familial depressive illness.

Cerebellar morphology in Tourette syndrome and obsessive-compulsive disorder.

Neuroanatomical and functional imaging studies have identified the cerebellum as an integral component of motor and language control. Few studies, however, have investigated the role of the cerebellum in Tourette syndrome (TS), a condition defined by the presence of semi‐involuntary movements and sounds.

Real-time rendering of translucent meshes

Subsurface scattering is important for photo-realistic rendering of translucent materials. We make approximations to the BSSRDF model and propose a simple lighting model to simulate the effects on translucent meshes. Our approximations are based on the observation that subsurface scattering is relatively local due to its exponential falloff.In the preprocessing stage we build subsurface scattering neighborhood information, which includes all the vertices within effective scattering range from each vertex. We then modify the traditional local illumination model into a run-time two-stage process. The first stage involves computation of reflection and transmission of light on surface vertices. The second stage bleeds in scattering effects from a vertexs neighborhood to generate the final result. We then merge the run-time two-stage process into a run-time single-stage process using precomputed integrals, and reduce the complexity of our run-time algorithm to O(N), where N is the number of vertices. The selection of the optimum set size for precomputed integrals is guided by a standard imagespace error-metric. Furthermore, we show how to compress the precomputed integrals using spherical harmonics. We compensate for the inadequacy of spherical harmonics for storing high frequency components by a reference points scheme to store high frequency components of the precomputed integrals explicitly. With this approach, we greatly reduce memory usage without loss of visual quality under a high-frequency lighting environment and achieve interactive frame rates for medium-sized scenes. Our model is able to capture the most important features of subsurface scattering: reflection and transmission due to multiple scattering.