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Nucleotide variants in cell type-specific gene regulatory elements in the human brain are risk factors for human disease. We measured chromatin accessibility in 1932 aliquots of sorted neurons and non-neurons from 616 human postmortem brains and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTLs). Only 10.4% of caQTLs are shared between neurons and non-neurons, which supports cell type-specific genetic regulation of the brain regulome. Incorporating allele-specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms that underlie disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs and identified the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides insights into disease etiology.

Structural variants (SVs) contribute to many disorders, yet, functionally annotating them remains a major challenge. Here, we integrate SVs with RNA-sequencing from human post-mortem brains to quantify their dosage and regulatory effects. We show that genic and regulatory SVs exist at significantly lower frequencies than intergenic SVs. Functional impact of copy number variants (CNVs) stems from both the proportion of genic and regulatory content altered and loss-of-function intolerance of the gene. We train a linear model to predict expression effects of rare CNVs and use it to annotate regulatory disruption of CNVs from 14,891 independent genome-sequenced individuals. Pathogenic deletions implicated in neurodevelopmental disorders show significantly more extreme regulatory disruption scores and if rank ordered would be prioritized higher than using frequency or length alone. This work shows the deleteriousness of regulatory SVs, particularly those altering CTCF sites and provides a simple approach for functionally annotating the regulatory consequences of CNVs.

Brain phenotypes showing environmental influence may help clarify unexplained associations between urban exposure and psychiatric risk. Heritable prefrontal fMRI activation during working memory (WM) is such a phenotype. We hypothesized that urban upbringing (childhood urbanicity) would alter this phenotype and interact with dopamine genes that regulate prefrontal function during WM. Further, dopamine has been hypothesized to mediate urban-associated factors like social stress. WM-related prefrontal function was tested for main effects of urbanicity, main effects of three dopamine genes-catechol-O-methyltransferase (COMT), dopamine receptor D1 (DRD1), and dopamine receptor D2 (DRD2)-and, importantly, dopamine gene-by-urbanicity interactions. For COMT, three independent human samples were recruited (total n = 487). We also studied 253 subjects genotyped for DRD1 and DRD2. 3T fMRI activation during the N-back WM task was the dependent variable, while childhood urbanicity, dopamine genotype, and urbanicity-dopamine interactions were independent variables. Main effects of dopamine genes and of urbanicity were found. Individuals raised in an urban environment showed altered prefrontal activation relative to those raised in rural or town settings. For each gene, dopamine genotype-by-urbanicity interactions were shown in prefrontal cortex-COMT replicated twice in two independent samples. An urban childhood upbringing altered prefrontal function and interacted with each gene to alter genotype-phenotype relationships. Gene-environment interactions between multiple dopamine genes and urban upbringing suggest that neural effects of developmental environmental exposure could mediate, at least partially, increased risk for psychiatric illness in urban environments via dopamine genes expressed into adulthood.

This article introduces regularized lineshape deconvolution in conjunction with TE-averaged PRESS spectroscopy to measure N-acetyl-aspartyl-glutamate (NAAG). Averaging different echo times suppressed the signals of multiplets from strongly coupled spin systems near 2 ppm; thus, minimizing the interfering signals to detect the acetyl proton signal of NAAG. Signal distortion was corrected by lineshape deconvolution, and Tikhonov regularization was introduced to reduce noise amplification arising from deconvolution; as a result, spectral resolution was enhanced without significantly sacrificing signal-to-noise ratio (SNR). This new approach was used to measure NAAG in the two regions of interest of healthy volunteers, dominated by gray matter and white matter, respectively. The acetyl proton signal of NAAG was directly quantified by fitting the deconvoluted spectra to a Voigt-lineshape spectral model function, yielding the NAAG-N-acetyl-aspartate (NAA) ratios of 0.11±0.02 for the gray matter voxels (n=8) and 0.18±0.02 for the white matter voxels (n=12)., (Copyright © 2011 Wiley-Liss, Inc.)

We review studies that have used diffusion imaging (DI) and magnetic resonance spectroscopy (MRS) to investigate genetic associations. A brief description of the measures obtainable with these methods and of some methodological and interpretability limitations is given. The usefulness of DI and MRS in defining intermediate phenotypes and in demonstrating the effects of common genetic variants known to increase risk for psychiatric manifestations on anatomical and metabolic phenotypes is reviewed. The main focus is on schizophrenia where the greatest amount of data has been collected. Moreover, we present an example coming from a different approach, where the genetic alteration is known (the deletion that causes Williams syndrome) and the DI phenotype can shed new light on the function of genes affected by the mutation. We conclude that, although these are still early days of this type of research and many findings remain controversial, both techniques can significantly contribute to the understanding of genetic effects in the brain and the pathophysiology of psychiatric disorders., (Published by Elsevier Inc.)

Background: A recent genome-wide association study linked a common variant in RELN (rs7341475G) with risk for schizophrenia in women. In the largest neuroimaging intermediate phenotype study reported so far, we evaluated the effect of rs7341475 on an extended array of different neuroscientific measures., Methods: Brain structure was evaluated with voxel-based morphometry and diffusion tensor imaging. Brain function during working memory was examined with functional magnetic resonance imaging. The RELN expression was determined in postmortem brain tissue of the dorsolateral prefrontal cortex and hippocampus. A total of 736 datasets were examined (voxel-based morphometry: n = 230, diffusion tensor imaging: n = 93, functional magnetic resonance imaging: n = 308, RELN expression: n = 105)., Results: Our analyses did not provide evidence for a significant main effect of gene or gene x sex interaction effect on any of the examined measures., Conclusions: This study does not suggest a significant impact of rs7341475 on brain structure, function, and RELN expression, arguing that this single nucleotide polymorphism and others linked with it do not affect brain measures related to the biology of schizophrenia., (Published by Elsevier Inc.)

The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3' UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy.

Little is known about genetic regulation of the development of white matter. This knowledge is critical in understanding the pathophysiology of neurodevelopmental syndromes associated with altered cognition as well as in elucidating the genetics of normal human cognition. The hemideletion of approximately 25 genes on chromosome 7q11.23 that causes Williams syndrome (WS) includes genes that regulate cytoskeletal dynamics in neurons, especially LIMK1 and CYLN2, and therefore offers the opportunity to investigate the role of these genes in the formation of white matter tracts. We used diffusion tensor imaging to demonstrate alteration in white matter fiber directionality, deviation in posterior fiber tract course, and reduced lateralization of fiber coherence in WS. These abnormalities are consistent with an alteration of the late stages of neuronal migration, define alterations of white matter structures underlying dissociable behavioral phenotypes in WS, and provide human in vivo information about genetic control of white matter tract formation.

The characterization of measurement error is critical in assessing the significance of diffusion tensor imaging (DTI) findings in longitudinal and cohort studies of psychiatric disorders. We studied 20 healthy volunteers, each one scanned twice (average interval between scans of 51 +/- 46.8 days) with a single shot echo planar DTI technique. Intersession variability for fractional anisotropy (FA) and Trace (D) was represented as absolute variation (standard deviation within subjects: SDw), percent coefficient of variation (CV) and intra-class correlation coefficient (ICC). The values from the two sessions were compared for statistical significance with repeated measures analysis of variance or a non-parametric equivalent of a paired t-test. The results showed good reproducibility for both FA and Trace (CVs below 10% and ICCs at or above 0.70 in most regions of interest) and evidence of systematic global changes in Trace between scans. The regional distribution of reproducibility described here has implications for the interpretation of regional findings and for rigorous pre-processing. The regional distribution of reproducibility measures was different for SDw, CV and ICC. Each one of these measures reveals complementary information that needs to be taken into consideration when performing statistical operations on groups of DT images.

Patient motion and image distortion induced by eddy currents cause artifacts in maps of diffusion parameters computed from diffusion-weighted (DW) images. A novel and comprehensive approach to correct for spatial misalignment of DW imaging (DWI) volumes acquired with different strengths and orientations of the diffusion sensitizing gradients is presented. This approach uses a mutual information-based registration technique and a spatial transformation model containing parameters that correct for eddy current-induced image distortion and rigid body motion in three dimensions. All parameters are optimized simultaneously for an accurate and fast solution to the registration problem. The images can also be registered to a normalized template with a single interpolation step without additional computational cost. Following registration, the signal amplitude of each DWI volume is corrected to account for size variations of the object produced by the distortion correction, and the b-matrices are properly recalculated to account for any rotation applied during registration. Both qualitative and quantitative results show that this approach produces a significant improvement of diffusion tensor imaging (DTI) data acquired in the human brain.

Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a genetic disorder that is characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury. To establish that DA deficiency is present in LND, the ligand WIN-35,428, which binds to DA transporters, was used to estimate the density of DA-containing neurons in the caudate and putamen of six patients with classic LND. Comparisons were made with 10 control subjects and 3 patients with Rett syndrome. Three methods were used to quantify the binding of the DA transporter so that its density could be estimated by a single dynamic positron emission tomography study. These approaches included the caudate- or putamen-to-cerebellum ratio of ligand at 80-90 min postinjection, kinetic analysis of the binding potential [Bmax/(Kd x Vd)] using the assumption of equal partition coefficients in the striatum and the cerebellum, and graphical analysis of the binding potential. Depending on the method of analysis, a 50-63% reduction of the binding to DA transporters in the caudate, and a 64-75% reduction in the putamen of the LND patients was observed compared to the normal control group. When LND patients were compared to Rett syndrome patients, similar reductions were found in the caudate (53-61%) and putamen (67-72%) in LND patients. Transporter binding in Rett syndrome patients was not significantly different from the normal controls. Finally, volumetric magnetic resonance imaging studies detected a 30% reduction in the caudate volume of LND patients. To ensure that a reduction in the caudate volume would not confound the results, a rigorous partial volume correction of the caudate time activity curve was performed. This correction resulted in an even greater decrease in the caudate-cerebellar ratio in LND patients when contrasted to controls. To our knowledge, these findings provide the first in vivo documentation of a dopaminergic reduction in LND and illustrate the role of positron emission tomography imaging in investigating neurodevelopmental disorders.

This paper presents the first Positron Emission Tomography (PET) images of the serotonin (5-hydroxytryptamine, 5-HT) transporter in the living human brain. PET imaging was performed in three healthy subjects after administration of [11C](+)McN5652 (the (+) enantiomer of trans-1,2,3,5,6,10 beta-hexahydro- 6-[4-(methylthio) phenyl]pyrrolo-[2,1-a] -isoquinolone), a radioligand previously shown to selectively label the 5-HT transporter in vivo in the mammalian (mouse and baboon) brain. To demonstrate the specificity of [11C](+)McN5652 binding, additional images were obtained in the same subjects after injection of [11C](-)McN5652, the pharmacologically inactive enantiomer, and, in two of the subjects, with [11C](+)McN5652 after pretreatment with the 5-HT uptake site blocker fluoxetine. Highest accumulation of [11C](+)McN5652 was observed in the midbrain, putamen, caudate nucleus, hypothalamus, and thalamus, regions known to contain high densities of 5-HT transporters. In these areas [11C](+)McN5652 concentrations rose steadily over 120 min. In contrast, with [11C](-)McN5652 and when the [11C](+)McN5652 binding was inhibited with fluoxetine, radioactivity concentrations declined after reaching a maximum (at 20 to 30 min). Inhibition studies with fluoxetine suggest that only with [11C](+)McN5652, there is specific binding. In the cerebellum, a region relatively void of 5-HT transporters, both [11C](+)McN5652 with and without fluoxetine block and [11C](-)McN5652 were released at approximately the same rate. The results of the studies indicate that [11C](+)McN5652 labels 5-HT transporter sites in the human brain. Quantitative PET imaging studies with this new tracer should provide valuable information on the status of these sites in health and disease.

We studied regional cerebral blood flow (rCBF) by xenon-133 dynamic single photon emission computed tomography (SPECT) in 17 normal volunteers who were performing the Wisconsin Card Sorting Test (WCST), a task that is particularly sensitive to disturbance of the prefrontal cortex, and a simple matching-to-sample task (BAR) as a sensorimotor control. Three methods for statistical analysis of regional "subtraction" data were used: absolute rCBF values, percent distribution values, and means adjusted for global CBF changes (covariance analysis). The absolute values had high variance, due to the combination of interindividual differences in global flow and intra-individual variation, and showed no statistically significant regional changes. This variation was greatly reduced by percent values and covariance analysis, which had quite similar outcomes. With both methods, significant increases of rCBF during the WCST as compared with the BAR were seen in the right anterior dorsolateral prefrontal and left occipital cortices, and reduction of rCBF in the left pararolandic region. Moreover, significant correlations with performance were found in the medial regions of the frontal lobes, with opposite trends for the right and left hemisphere. The posterior dorsolateral prefrontal region showed a negative correlation with sensory-motor frequency, an index related to the task's difficulty. These results are consistent with previous findings using other rCBF techniques and confirm the statistical advantage of normalization and covariance methods, which yield practically identical results, at least in this analysis based on regions of interest.

Objective: To investigate both rCBF and cerebrovascular reactivity, evaluated as pre- and post-ACZ rCBF differences in a group of IDDM patients with differences in duration of disease and severity of complications., Research Design and Methods: rCBF was measured by the 133Xenon inhalation method in 20 IDDM patients and in 15 healthy control subjects before and after an intravenous injection of ACZ, a carbonic anhydrase inhibitor commonly used to assess cerebrovascular reactivity., Results: Basal global CBF (the mean of 32 regional values) was within the normal range in all patients but 1, who showed slight hyperperfusion; moreover, in 3 patients with long-lasting disease, some hypoperfused regions were found. ANOVA showed an inverse correlation between basal global CBF (P < 0.01) and duration of diabetes, but no correlation with Hb, MABP, serum glucose concentration, or GHb. Compared with control subjects, the percentage of global CBF increment after ACZ administration was significantly impaired in 4 patients and gave a borderline response in 2 patients; 4 of these poor ACZ responders had retinopathy, and 1 had suffered from a TIA. Duration of diabetes, Hb, MABP, serum glucose concentration, and GHb did not correlate with the percentage of post-ACZ global CBF changes, and did not differ among the 6 poor ACZ responders and the other diabetic patients or control subjects., Conclusions: These results confirm that global CBF is within the normal range in most IDDM patients, although it is significantly influenced by the duration of diabetes; pathophysiological correlates of the altered cerebrovascular reactivity need to be further investigated. rCBF measurements, before and after ACZ administration, seem to represent a safe and reliable tool for assessing cerebrovascular function in IDDM.

Background and Purpose: The aim of this study was to investigate regional cerebral blood flow parameters during the postacute phase of unilateral ischemic stroke and to correlate them with clinical data., Methods: Regional cerebral blood flow was measured in 187 patients in the stabilized phase of stroke by the xenon-133 inhalation method with 32 extracranial detectors. Thirty-eight patients were reexamined after a mean +/- SD time of 32 +/- 21.4 months., Results: The overall detection of hypoperfusion was 92.0%, with asymmetries as the most sensitive index, especially for patients with a lesser degree of neurological disability. Neurological disability score was strongly associated with regional cerebral blood flow in the affected hemisphere (p < 0.0001) and with asymmetries (p < 0.0001). The presence of carotid obstruction further decreased the regional cerebral blood flow in the affected hemisphere and significantly increased asymmetry (p < 0.0001). Subjects who had no hypoperfusion at absolute values analysis were more frequently free of carotid disease and had less severe disability than those who had bilateral or unilateral regional absolute cerebral blood flow reduction. In 38 patients without new cerebrovascular events, a significant (p = 0.005) reduction of hemispheric regional cerebral blood flow asymmetries was found on a follow-up examination., Conclusions: These data confirm the value of regional cerebral blood flow asymmetries in stroke detection and point out that important clinical information is also contained in absolute values analysis.

Phantom studies and cerebral blood flow (CBF) measurements in 11 normal subjects at rest were performed by single photon emission tomography (SPECT) with Xe-133 (16 mm full-width at half-maximum [FWHM] collimation) and Xe-127 (16 mm, 12 mm, and 9 mm FWHM collimation). The phantom results clearly illustrated the feasibility of Xe-127 studies and the advantage of Xe-127 over Xe-133 for equivalent patient dose exposures. CBF values obtained with Xe-127 were comparable to those of Xe-133 for the 16 mm collimator, although higher flow values were found with the better resolution, probably because of reduced partial volume effects. The correlations between the various groups of examinations were high, except for the Xe-133 and Xe-127 16 mm collimator groups. Xe-127 allows a considerable increase in the resolution of the images, while exposing the patient to a lower radiation dose. Potential limitations because of higher energy penetrating photons from Xe-127 were not observed in this specially shielded equipment.

Quantified electroencephalogram (EEG) and regional cerebral blood flow (rCBF) measurements are reliable and currently employed techniques in the functional exploration of the aging brain; they can be routinely employed, since discomfort to the patient is minimal. Topographical analysis of EEG and rCBF results is performed in our laboratory by a fully automated mapping system, which also enables statistical comparisons in real time. The goal of our study is to ascertain if there are systematic modifications in the topographic distribution of rCBF and EEG parameters in normal aging, dementia, cerebrovascular disease and in conditions of increased risk for cerebral pathology (e.g. hypertension). Dementias and cerebrovascular pathologies present characteristic brain functional abnormalities, which can be detected by comparing the patient data to an age-matched normal population by the appropriate statistical tests; therefore, the accurate selection of healthy aged controls appears as a crucial issue in order to improve the sensitivity of statistics.

Patient motion and image distortion induced by eddy currents cause artifacts in maps of diffusion parameters computed from diffusion-weighted (DW) images. A novel and comprehensive approach to correct for spatial misalignment of DW imaging (DWI) volumes acquired with different strengths and orientations of the diffusion sensitizing gradients is presented. This approach uses a mutual information-based registration technique and a spatial transformation model containing parameters that correct for eddy current-induced image distortion and rigid body motion in three dimensions. All parameters are optimized simultaneously for an accurate and fast solution to the registration problem. The images can also be registered to a normalized template with a single interpolation step without additional computational cost. Following registration, the signal amplitude of each DWI volume is corrected to account for size variations of the object produced by the distortion correction, and the b-matrices are properly recalculated to account for any rotation applied during registration. Both qualitative and quantitative results show that this approach produces a significant improvement of diffusion tensor imaging (DTI) data acquired in the human brain. Magn Reson Med 51:103–114, 2004. Published 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]