The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism.

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies.

OBJECTIVE: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids. DESIGN AND METHODS: We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42 000) and twelve SNPs in African Americans (N up to 5800). RESULTS: After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104 kg m(-2) greater, waist was 0.305 cm larger and hip was 0.168 cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107 kg m(-2) greater for BMI (interaction P=0.0001), 0.267 cm for waist (interaction P=0.001) and 0.21 cm for hip (interaction P=0.001). No other significant interactions were observed. CONCLUSION: Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.

The contribution of noise to contrast invariance of orientation tuning in cat visual cortex.

Feedforward models of visual cortex appear to be inconsistent with a well-known property of cortical cells: contrast invariance of orientation tuning. The models' fixed threshold broadens orientation tuning as contrast increases, whereas in real cells tuning width is invariant with contrast. We have compared the orientation tuning of spike and membrane potential responses in single cells. Both are contrast invariant, yet a threshold-linear relation applied to the membrane potential accurately predicts the orientation tuning of spike responses. The key to this apparent paradox lies in the noisiness of the membrane potential. Responses that are subthreshold on average are still capable of generating spikes on individual trials. Unlike the iceberg effect, contrast invariance remains intact even as threshold narrows orientation selectivity. Noise may, by extension, smooth the average relation between membrane potential and spike rate throughout the brain.

Increased Functional Connectivity After Listening to Favored Music in Adults With Alzheimer Dementia.

BACKGROUND: Personalized music programs have been proposed as an adjunct therapy for patients with Alzheimer disease related dementia, and multicenter trials have now demonstrated improvements in agitation, anxiety, and behavioral symptoms. Underlying neurophysiological mechanisms for these effects remain unclear. METHODS: We examined 17 individuals with a clinical diagnosis of Alzheimer disease related dementia using functional MRI following a training period in a personalized music listening program. RESULTS: We find that participants listening to preferred music show specific activation of the supplementary motor area, a region that has been associated with memory for familiar music that is typically spared in early Alzheimer disease. We also find widespread increases in functional connectivity in corticocortical and corticocerebellar networks following presentation of preferred musical stimuli, suggesting a transient effect on brain function. CONCLUSIONS: Findings support a mechanism whereby attentional network activation in the brain's salience network may lead to improvements in brain network synchronization.

Prediction of orientation selectivity from receptive field architecture in simple cells of cat visual cortex.

From the intracellularly recorded responses to small, rapidly flashed spots, we have quantitatively mapped the receptive fields of simple cells in the cat visual cortex. We then applied these maps to a feedforward model of orientation selectivity. Both the preferred orientation and the width of orientation tuning of the responses to oriented stimuli were well predicted by the model. Where tested, the tuning curve was well predicted at different spatial frequencies. The model was also successful in predicting certain features of the spatial frequency selectivity of the cells. It did not successfully predict the amplitude of the responses to drifting gratings. Our results show that the spatial organization of the receptive field can account for a large fraction of the orientation selectivity of simple cells.

Dynamics of the orientation-tuned membrane potential response in cat primary visual cortex.

Neurons in the primary visual cortex are highly selective for stimulus orientation, whereas their thalamic inputs are not. Much controversy has been focused on the mechanism by which cortical orientation selectivity arises. Although an increasing amount of evidence supports a linear model in which orientation selectivity is conferred upon visual cortical cells by the alignment of the receptive fields of their thalamic inputs, the controversy has recently been rekindled with the suggestion that late cortical input--delayed by multiple synapses--could lead to sharpening of orientation selectivity over time. Here we used intracellular recordings in vivo to examine temporal properties of the orientation-selective response to flashed gratings. Bayesian parameter estimation demonstrated that both preferred orientation and tuning width were stable throughout the response to a single stimulus.

Multivariate characterization of white matter heterogeneity in autism spectrum disorder.

The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders.

Computational identification of cis-acting elements affecting post-transcriptional control of gene expression in Saccharomyces cerevisiae.

Understanding the regulation of gene expression requires the identification of cis -acting control elements that modulate gene function. The recent availability of complete genome sequences and profiles of mRNA expression has facilitated the development and utilization of computational methods to identify discrete regulatory elements. We have developed an oligomer counting method that identifies sequences that occur significantly more often in a group of interest relative to other genes in the genome. The use of a second parameter, which measures the frequency of oligomers within the group of interest, allows the detection of false positive signals caused by very infrequent oligomers that would otherwise appear as significant. Applying this method to gene groups that have a common expression pattern or shared function should identify oligomers that comprise cis -acting control elements. As a test of this method, we applied this approach to a set of intron-containing yeast genes, where we easily identified the known splicing signals as control elements. We have used this training set to examine how this method is affected by the length of the oligomer examined, as well as the size and composition of the gene group. These simulations allowed us to identify rules for selecting groups of genes to analyze. Finally, application of this method to nuclear genes encoding proteins targeted to the mitochondria identified a new putative cis -acting sequence in the 3'-untranslated region of this family of genes, which may play a role in mRNA localization or the regulation of mRNA stability or translation.

PROSPECT improves cis-acting regulatory element prediction by integrating expression profile data with consensus pattern searches.

Consensus pattern and matrix-based searches designed to predict cis-acting transcriptional regulatory sequences have historically been subject to large numbers of false positives. We sought to decrease false positives by incorporating expression profile data into a consensus pattern-based search method. We have systematically analyzed the expression phenotypes of over 6000 yeast genes, across 121 expression profile experiments, and correlated them with the distribution of 14 known regulatory elements over sequences upstream of the genes. Our method is based on a metric we term probabilistic element assessment (PEA), which is a ranking of potential sites based on sequence similarity in the upstream regions of genes with similar expression phenotypes. For eight of the 14 known elements that we examined, our method had a much higher selectivity than a naïve consensus pattern search. Based on our analysis, we have developed a web-based tool called PROSPECT, which allows consensus pattern-based searching of gene clusters obtained from microarray data.

High-throughput synthesis and characterization of nanocrystalline porphyrinic zirconium metal-organic frameworks.

We describe and employ a high-throughput screening method to accelerate the synthesis and identification of pure-phase, nanocrystalline metal-organic frameworks (MOFs). We demonstrate the efficacy of this method through its application to a series of porphyrinic zirconium MOFs, resulting in the isolation of MOF-525, MOF-545, and PCN-223 on the nanoscale.

Membrane potential and conductance changes underlying length tuning of cells in cat primary visual cortex.

Spike responses for many cells of cat primary visual cortex are optimized for the length of a drifting grating stimulus. Stimuli that are longer or shorter than this optimal length elicit submaximal spike responses. To investigate the mechanisms responsible for this length tuning, we have recorded intracellularly from visual cortical neurons in the cat while presenting drifting grating stimuli of varying lengths. We have found that the membrane potential responses of the cells also exhibit length tuning, but that the suppression of spike responses at lengths longer than the preferred is 30-50% stronger than the corresponding suppression of the membrane potential responses. This difference may be attributed to the effects of spike threshold. Furthermore, using steady injected currents, we have measured changes in the excitatory and inhibitory components of input conductance evoked by stimuli of different lengths. We find that, compared with optimal stimuli, long stimuli evoke both an increase in inhibitory conductance and a decrease in excitatory conductance. These two mechanisms differ in their contrast sensitivity, resulting in stronger end stopping and shorter optimal lengths for high-contrast stimuli. These patterns suggest that response suppression for long stimuli is generated by a combination of active inhibition from stimuli outside the excitatory receptive field, as well as decreased excitation from other cortical cells that are themselves end-inhibited.

Effects of angiotensin converting enzyme inhibition with cilazapril on intimal hyperplasia in injured arteries and vascular grafts in the baboon.

To determine the importance of angiotensin converting enzyme (ACE) activity in the development of arterial proliferative lesions in a primate model, the response to vascular injury was studied in five baboons treated with oral cilazapril (20 mg/kg/day) and in five untreated control animals. Each animal underwent three procedures: 1) carotid artery endarterectomy, 2) balloon catheter deendothelialization of the superficial femoral artery, and 3) surgical placement of bilateral aorto-iliac expanded polytetrafluoroethylene (Gore-Tex) vascular grafts. Cilazapril therapy was initiated 1 week preoperatively and continued throughout the study interval. At 1 and 3 weeks postoperatively, plasma ACE activity was inhibited by more than 96% versus control values. After animals were killed at 3 months, injured vessel and graft segments were evaluated morphometrically. Although the response between animals was variable, average cross-sectional areas of neointima did not differ between the cilazapril-treated and control groups at sites of carotid endarterectomy (0.26 +/- 0.12 versus 0.34 +/- 0.17 mm2, respectively; p greater than 0.5), femoral artery ballooning (0.15 +/- 0.08 versus 0.11 +/- 0.01 mm2; p greater than 0.5), or at graft anastomoses (1.86 +/- 0.50 versus 1.72 +/- 0.50 mm2; p greater than 0.5). Thus, cilazapril did not reduce intimal thickening over 3 months in these primate arterial injury models. However, a possible beneficial effect of cilazapril, which might be apparent at earlier time points or with larger animal groups, cannot be excluded.

Quantitative reverse transcription-polymerase chain reaction of circulating thyroglobulin messenger ribonucleic acid for monitoring patients with thyroid carcinoma.

Patients with thyroid cancer are monitored for disease recurrence by measurement of serum thyroglobulin (Tg) and iodine-131 (131I) scanning. To enhance sensitivity and to circumvent antibodies that interfere with Tg immunoassays, we have developed RT-PCR assays that detect circulating thyroid messenger RNA (mRNA) transcripts. We now report results using a sensitive quantitative Tg mRNA assay (Taqman; ABI, Foster City, CA) in comparison with immunoassay in patients previously treated for thyroid cancer. We evaluated 107 patients: 84 during T4 therapy, 14 after T4 withdrawal, and 9 at both time points. All patients had near-total thyroidectomy, and 92% received postoperative 131I. Serum TSH, Tg protein, and Tg mRNA were measured. Patients were grouped based on most recent 131I scan or pathologically confirmed disease as having no detectable thyroid tissue (n = 33), thyroid bed uptake (n = 37), cervical/regional adenopathy (n = 21), or distant metastases (n = 16). During T4 therapy, median (range) Tg mRNA values (pg Tg Eq/microg thyroid RNA) for the groups were 1.5 (0-26.8), 9.4 (0.5-90.0), 15.4 (0.2-92), and 12.4 (1.9-16.6), respectively. Using a value of 3 pg Tg Eq/microg thyroid RNA as cut-point, Tg mRNA was positive in 38% of patients with no uptake, 75% with thyroid bed uptake, 84% with cervical/regional disease, and 94% with distant metastases. The median Tg mRNA value for patients with no uptake was lower than the median values for patients with thyroid bed uptake (P = 0.009) or with detectable thyroid tissue at any site (P = 0.010). Patients with negative 131I whole body scans were also less likely to have detectable Tg mRNA levels than were patients with thyroid bed uptake (P < 0.001) or any detectable thyroid tissue at any location (P < 0.001). Similar differences between these groups were seen after T4 withdrawal and for the 23 patients with circulating anti-Tg antibodies, when analyzed separately. Eight of the nine patients studied with low and high TSH concentrations displayed greater amounts of circulating Tg mRNA after T4 withdrawal. In three patients followed prospectively, the amount Tg mRNA correlated with the presence and absence of cervical metastases. In conclusion, we have demonstrated that a quantitative Tg mRNA assay can identify thyroid cancer patients with recurrent or residual thyroid tissue with greater sensitivity and similar specificity to Tg immunoassay during T4 therapy. The assay was unaffected by anti-Tg antibodies, responded to TSH-stimulation, and was reduced after surgical removal of metastases. These data suggest that this quantitative Tg mRNA assay may be a sensitive marker of tumor recurrence or response to therapy, particularly in patients with anti-Tg antibodies.

In vitro endothelialization of small-caliber vascular grafts.

To establish the conditions for achieving immediate and complete endothelial cell coverage of the luminal surfaces of small-caliber (internal diameter:4 mm) vascular grafts in vitro, the attachment and spread of endothelial cells cultured from human umbilical veins to expanded polytetrafluoroethylene (PTFE) and knitted Dacron grafts was studied. Cell number was quantified by fluorescent measurements of deoxyribonucleic acid. The completeness of cell coverage and cell junction formation were assessed by means of both scanning and transmission electron microscopy. Cell attachment was compared after expanded PTFE or knitted Dacron grafts were precoated with gelatin, laminin, fibronectin, fibrin, or collagen, singly or in combination. Saturation cell attachment of 3.5 +/- 0.7 X 10(5) cm-2 was completed within 15 minutes when (1) type I collagen was used to form the substrate matrix, (2) human umbilical vein endothelial cells were suspended in phosphate-buffered saline solution supplemented with calcium and magnesium, and (3) the suspended cell number was greater than or equal to 5 X 10(5). In contrast, attachment to untreated or laminin-treated surfaces was 1.3 +/- 0.33 X 10(5) cells cm-2 and attachment to fibrin- or fibronectin-treated surfaces was 2.8 +/- 0.47 and 2.4 +/- 1.1 cells X 10(5) cm-2, respectively. However, to produce a confluent flow surface, the attached cells required several hours in culture medium to spread completely. Maintenance of confluent cell coverage on the graft surface for 3 days in vitro was achieved by means of continuous perfusion with oxygenated tissue culture medium RPMI-1640-HEPES supplemented with 20% fetal bovine serum. We conclude that optimum immediate confluent endothelial coverage of small-caliber vascular grafts requires a high concentration of cells, attachment to collagen-precoated grafts, and several hours of incubation in complete culture medium.

Aspirin-independent antithrombotic effects of acutely attached cultured endothelial cells on endarterectomized arteries.

We have compared the acute antithrombotic effects of aspirin-treated versus normal endothelial cell (EC) coverage of endarterectomized baboon aortic segments (EAS) incorporated into chronic exteriorized arteriovenous shunts in baboons. Human ECs grown in culture were incubated in control medium or medium containing aspirin (100 mumols/ml) and then attached at saturation density by incubating EC suspensions (6 x 10(5) cells/100 microliters) within EAS for 20 minutes. Nonendarterectomized aortic segments and untreated EAS served as negative and positive controls, respectively. The inhibitory effect of aspirin treatment on EC production of prostacyclin was confirmed by radioimmunoassay of its stable metabolic breakdown product, 6-keto-prostaglandin F1 alpha in supernatant medium. Thrombus formation in vivo was measured as the accumulation of indium 111-labeled platelets on endarterectomy sites in real time by scintillation camera imaging. 111In-labeled platelets were deposited rapidly, reaching a plateau by 60 minutes of 4.40 +/- 0.89 x 10(9) platelets/cm, compared with 111In-labled platelet deposition on nonendarterectomized segments of 0.89 +/- 0.26 x 10(9) platelets/cm (p = 0.008). Coverage of EAS with normal cultured ECs significantly reduced platelet deposition on EAS (1.05 +/- 0.45 x 10(9) platelets/cm; p = 0.009 at 1 hour compared with EAS not incubated with ECs). Aspirin-treated ECs also produced a marked reduction in platelet disposition (0.71 +/- 0.24 x 10 platelets/cm; p = 0.007 compared with EAS without ECs) that was equivalent to the effect of non-aspirin-treated ECs (p greater than 0.5). Scanning and transmission electron microscopy confirmed the antithrombotic effects of attached ECs. We conclude that endarterectomy of normal arteries produces a highly thrombogenic surface and the thrombogenicity is abolished by acutely attaching cultured human ECs.

Brain tumor resection aided with markers placed using stereotaxis guided by magnetic resonance imaging and computed tomography.

In the operative resection of brain tumors, defining and locating edges of deep-seated tumors or those with indistinct color and consistency can be difficult. This report presents a simple yet precise, alternative method, using the basic Brown-Roberts-Wells or Cosman-Roberts-Wells stereotactic frame, for placement of visual markers to aid in tumor resections. The method can also be extended to the Leksell system. Using routine computed tomographic scanning or magnetic resonance imaging after stereotactic frame application, multiple points along tumor edges were used as target points. In the operating room, standard techniques were used for the skin incision, removal of the bone flap, and opening the dura. At each target point, after opening the dura and using stereotactic coordinates and equipment, a microbiopsy forceps was used to place "micropatties" (each with a string tail) or small catheters with pledgets or catheter tips located at tumor edges. After removing the arc, the tumor resection was accomplished in a conventional nonstereotactic manner by simply following string tails or catheters to the tumor. Gross tumor edges were determined from positions of actual patties or catheter tips. These simple but accurate techniques offer the possibility of tumor resections under stereotactic guidance with equipment readily available to most neurosurgeons. The fidelity of marker placement is also maintained in relation to tumor edges despite shifts in the tumor and/or brain as cystic areas are drained or large amounts of the tumor are resected.

Regional differences in bone density of young men involved in different exercises.

In this cross-sectional, retrospective study, the bone mineral content (BMC) and density (BMD) of the whole skeleton, upper limbs, lower limbs, femoral neck, and lumbar vertebrae were measured using dual photon absorptiometry and the results compared in healthy young males involved in: weight-lifting, running, cross-training, or recreational exercises. When adjusted for body weight, the upper limb BMD was highest in those engaged solely in weight-lifting (mean 1.021, SE 0.019, and 95% CI 0.981-1.061) and lowest in runners (mean 0.908, SE 0.019 and 95% CI 0.869-0.946). These differences were significant (P = 0.0004). There were no significant differences in upper limb BMD between weight-lifters and cross-trained athletes and between runners and those engaged in recreational exercises. Significant differences in BMD were observed between weight-lifters and recreational athletes (P = 0.001) and between cross-trained athletes and runners (P = 0.03). No other significant differences were observed. These data suggest that healthy, young, adult males reporting a history of intensive weight-lifting had significantly greater bone mass of the upper limb bones than those reporting a history of non-weight-lifting exercises. These results imply a specific versus generalized effect of mechanical load on bones of the skeleton.

Joubert's syndrome and prenatal hydrocephalus.

Joubert's syndrome is an autosomal-recessive condition characterized by dysgenesis of the cerebellar vermis, hypotonia, developmental delay, a respiratory pattern of alternating tachypnea and apnea, and abnormal eye movements. Radiologic findings include a midline cerebellar cleft in place of the vermis and a characteristic shape of the fourth ventricle. Prenatal hydrocephalus has been proposed as a possible etiology for the cerebellar abnormalities but has not previously been described in association with this syndrome. The authors report a patient with clinical and radiographic features consistent with Joubert's syndrome who presented with congenital hydrocephalus.

Primary CNS malignant rhabdoid tumor (MRT): report of two cases and review of literature.

Primary CNS rhabdoid tumor is an enigmatic and extremely rare malignant tumor of early childhood, probably embryonal, that has often been histopathologically classified together with rhabdoid tumor of kidneys or other organs in infants. Only four previously documented cases of primary CNS malignant rhabdoid tumor (MRT) were found in the literature. We report two cases of primary CNS MRT with biopsy and complete autopsy findings that share close clinicopathologic, immunohistochemical and ultrastructural similarities between the two. It is concluded that the primary CNS MRT is an entity which is extremely malignant, easily mistaken as a primitive neuroectodermal tumor, and potentially derives from a meningothelial precursor cell which is embryonally equal to the serosal mesothelial precursor cells which surround the kidneys and other organs. Hence, it tends to anatomically occur at the location of abundant meningeal infoldings such as the cerebellar cortex and may be diffuse or multicentric in its meningeal involvement. Furthermore, it may concurrently or multicentrically occur in association with MRT originating from the serosal membrane of other organs, such as the kidney.