Brain charts for the human lifespan.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder.

Maternal immune activation (MIA) via infection during pregnancy is known to increase risk for autism spectrum disorder (ASD). However, it is unclear how MIA disrupts fetal brain gene expression in ways that may explain this increased risk. Here we examine how MIA dysregulates rat fetal brain gene expression (at a time point analogous to the end of the first trimester of human gestation) in ways relevant to ASD-associated pathophysiology. MIA downregulates expression of ASD-associated genes, with the largest enrichments in genes known to harbor rare highly penetrant mutations. MIA also downregulates expression of many genes also known to be persistently downregulated in the ASD cortex later in life and which are canonically known for roles in affecting prenatally late developmental processes at the synapse. Transcriptional and translational programs that are downstream targets of highly ASD-penetrant FMR1 and CHD8 genes are also heavily affected by MIA. MIA strongly upregulates expression of a large number of genes involved in translation initiation, cell cycle, DNA damage and proteolysis processes that affect multiple key neural developmental functions. Upregulation of translation initiation is common to and preserved in gene network structure with the ASD cortical transcriptome throughout life and has downstream impact on cell cycle processes. The cap-dependent translation initiation gene, EIF4E, is one of the most MIA-dysregulated of all ASD-associated genes and targeted network analyses demonstrate prominent MIA-induced transcriptional dysregulation of mTOR and EIF4E-dependent signaling. This dysregulation of translation initiation via alteration of the Tsc2-mTor-Eif4e axis was further validated across MIA rodent models. MIA may confer increased risk for ASD by dysregulating key aspects of fetal brain gene expression that are highly relevant to pathophysiology affecting ASD.

The influence of magnetic order on the magnetoresistance anisotropy of Fe1 + δ-x Cu x Te.

We performed resistance measurements on [Formula: see text]Cu x Te with [Formula: see text] in the presence of in-plane applied magnetic fields, revealing a resistance anisotropy that can be induced at a temperature far below the structural and magnetic zero-field transition temperatures. The observed resistance anisotropy strongly depends on the field orientation with respect to the crystallographic axes, as well as on the field-cooling history. Our results imply a correlation between the observed features and the low-temperature magnetic order. Hysteresis in the angle-dependence indicates a strong pinning of the magnetic order within a temperature range that varies with the Cu content. The resistance anisotropy vanishes at different temperatures depending on whether an external magnetic field or a remnant field is present: the closing temperature is higher in the presence of an external field. For [Formula: see text] the resistance anisotropy closes above the structural transition, at the same temperature at which the zero-field short-range magnetic order disappears and the sample becomes paramagnetic. Thus we suggest that under an external magnetic field the resistance anisotropy mirrors the magnetic order parameter. We discuss similarities to nematic order observed in other iron pnictide materials.

The effects of post-growth annealing on the structural and magnetic properties of BaFe2As2.

We investigate the effects of post-growth annealing on the structural and magnetic properties of BaFe2As2. Magnetic susceptibility measurements, which exhibit a signal corresponding to the magnetic phase transition, and high-resolution x-ray diffraction measurements, which directly probe the structural order parameter, show that annealing causes the ordering temperatures of both the phase transitions to increase, sharpen and converge. In the as grown sample, our measurements show two distinct transitions corresponding to structural and magnetic ordering, which are separated in temperature by approximately 1 K. After 46 days (d) of annealing at 700 °C, the two become concurrent in temperature. These measurements demonstrate that the structural phase transition is second-order like when the magnetic and structural phase transitions are separated in temperature, and first-order like when the two phase transition temperatures coincide. This observation indicates that annealing causes the system to cross a hitherto undiscovered tricritical point. In addition, x-ray diffraction measurements show that the c-axis lattice parameter increases with annealing up to 30 d, but remains constant for longer annealing times. Comparisons of BaFe2As2 to SrFe2As2 are made when possible.

Bandwidth and Electron Correlation-Tuned Superconductivity in Rb_{0.8}Fe_{2}(Se_{1-z}S_{z})_{2}.

We present a systematic angle-resolved photoemission spectroscopy study of the substitution dependence of the electronic structure of Rb_{0.8}Fe_{2}(Se_{1-z}S_{z})_{2} (z=0, 0.5, 1), where superconductivity is continuously suppressed into a metallic phase. Going from the nonsuperconducting Rb_{0.8}Fe_{2}S_{2} to superconducting Rb_{0.8}Fe_{2}Se_{2}, we observe little change of the Fermi surface topology, but a reduction of the overall bandwidth by a factor of 2. Hence, for these heavily electron-doped iron chalcogenides, we have identified electron correlation as explicitly manifested in the quasiparticle bandwidth to be the important tuning parameter for superconductivity, and that moderate correlation is essential to achieving high T_{C}.

Effect of electron correlations on magnetic excitations in the isovalently doped iron-based superconductor Ba(Fe(1-x)Ru(x))(2)As(2).

Magnetic correlations in isovalently doped Ba(Fe(1-x)Ru(x))(2)As(2) (x = 0.25, T(c) = 14.5 K; x = 0.35, T(c) = 20 K) are studied by elastic and inelastic neutron scattering techniques. A relatively large superconducting spin gap accompanied by a weak resonance mode is observed in the superconducting state in both samples. In the normal state, the magnetic excitation intensity is dramatically reduced with increasing Ru doping toward the optimally doped regime. Our results favor that the weakening of the electron-electron correlations by Ru doping is responsible for the dampening of the resonance mode, as well as the suppression of the normal state antiferromagnetic correlations near the optimally doped regime in this system.

Neutron-diffraction measurements of an antiferromagnetic semiconducting phase in the vicinity of the high-temperature superconducting state of K(x)Fe(2-y)Se2.

The recently discovered K-Fe-Se high-temperature superconductor has caused heated debate regarding the nature of its parent compound. Transport, angle-resolved photoemission spectroscopy, and STM measurements have suggested that its parent compound could be insulating, semiconducting, or even metallic [M. H. Fang, H.-D. Wang, C.-H. Dong, Z.-J. Li, C.-M. Feng, J. Chen, and H. Q. Yuan, Europhys. Lett. 94, 27009 (2011); F. Chen et al., Phys. Rev. X 1, 021020 (2011); and W. Li et al., Phys. Rev. Lett. 109, 057003 (2012)]. Because the magnetic ground states associated with these different phases have not yet been identified and the relationship between magnetism and superconductivity is not fully understood, the real parent compound of this system remains elusive. Here, we report neutron-diffraction experiments that reveal a semiconducting antiferromagnetic (AFM) phase with rhombus iron vacancy order. The magnetic order of the semiconducting phase is the same as the stripe AFM order of the iron pnictide parent compounds. Moreover, while the sqrt[5]×sqrt[5] block AFM phase coexists with superconductivity, the stripe AFM order is suppressed by it. This leads us to conjecture that the new semiconducting magnetic ordered phase is the true parent phase of this superconductor.

Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism.

Maternal 15q11-q13 duplication is the most common copy number variant in autism, accounting for ∼1-3% of cases. The 15q11-q13 region is subject to epigenetic regulation, and genomic copy number losses and gains cause genomic disorders in a parent-of-origin-specific manner. One 15q11-q13 locus encodes the GABA(A) receptor ß3 subunit gene (GABRB3), which has been implicated by several studies in both autism and absence epilepsy, and the co-morbidity of epilepsy in autism is well established. We report that maternal transmission of a GABRB3 signal peptide variant (P11S), previously implicated in childhood absence epilepsy, is associated with autism. An analysis of wild-type and mutant ß3 subunit-containing α1ß3γ2 or α3ß3γ2 GABA(A) receptors shows reduced whole-cell current and decreased ß3 subunit protein on the cell surface due to impaired intracellular ß3 subunit processing. We thus provide the first evidence of an association between a specific GABA(A) receptor defect and autism, direct evidence that this defect causes synaptic dysfunction that is autism relevant and the first maternal risk effect in the 15q11-q13 autism duplication region that is linked to a coding variant.

Reduced minicolumns in the frontal cortex of patients with autism.

Cell minicolumns were shown to be narrower in frontal regions in brains of autistic patients compared with controls. This was not found in primary visual cortex. Within the frontal cortex, dorsal and orbital regions displayed the greatest differences while the mesial region showed the least change. We also found that minicolumns in the brain of a 3-year-old autistic child were indistinguishable from those of the autistic adult in two of three frontal regions, in contrast to the control brains. This may have been due to the small size of the columns in the adult autistic brain rather than to an accelerated development. The presence of narrower minicolumns supports the theory that there is an abnormal increase in the number of ontogenetic column units produced in some regions of the autistic brain during corticoneurogenesis.

Autism as a disorder of neural information processing: directions for research and targets for therapy.

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.

Transmission disequilibrium testing of arginine vasopressin receptor 1A (AVPR1A) polymorphisms in autism.

Impairment in social reciprocity is a central component of autism. In preclinical studies, arginine vasopressin (AVP) has been shown to increase a range of social behaviors, including affiliation and attachment, via the V(1a) receptor (AVPR1A) in the brain. Both the behavioral effects of AVP and the neural distribution of the V1a receptor vary greatly across mammalian species. This difference in regional receptor expression as well as differences in social behavior may result from a highly variable repetitive sequence in the 5' flanking region of the V1a gene (AVPR1A). Given this comparative evidence for a role in inter-species variation in social behavior, we explored whether within our own species, variation in the human AVPR1A may contribute to individual variations in social behavior, with autism representing an extreme form of social impairment. We genotyped two microsatellite polymorphisms from the 5' flanking region of AVPR1A for 115 autism trios and found nominally significant transmission disequilibrium between autism and one of the microsatellite markers by Multiallelic Transmission/Disequilibrium test (MTDT) that was not significant after Bonferroni correction. We also screened approximately 2 kb of the 5' flanking region and the coding region and identified 10 single nucleotide polymorphisms.

Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder.

The serotonin transporter gene (SLC6A4, MIM 182138) is a candidate gene in autistic disorder based on neurochemical, neuroendocrine studies and the efficacy of potent serotonin transporter inhibitors in reducing ritualistic behaviors and related aggression. An insertion/deletion polymorphism (5-HTTLPR) in the promoter region and a variable number of tandem repeat polymorphism (VNTR) in the second intron, were previously identified and suggested to modulate transcription. Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium. In the present study, TDT was conducted in 81 new trios. A previous finding of transmission disequilibrium between a haplotype consisting of the 5-HTTLPR and intron 2 VNTR was replicated in this study, but not preferential transmission of 5-HTTLPR as an independent marker. Because of inconsistent transmission of 5-HTTLPR across studies, SLC6A4 and its flanking regions were sequenced in 10 probands, followed by typing of 20 single nucleotide polymorphisms (SNPs) and seven simple sequence repeat (SSR) polymorphisms in 115 autism trios. When individual markers were analyzed by TDT, seven SNP markers and four SSR markers (six SNPs, 5-HTTLPR and the second intron VNTR from promoter 1A through intron 2 of SLC6A4, one SSR from intron 7 of SLC6A4, one SNP from the bleomycin hydrolase gene (BLMH, MIM 602403) and one SSR telomeric to BLMH) showed nominally significant evidence of transmission disequilibrium. Four markers showed stronger evidence of transmission disequilibrium (TDT(max) P = 0.0005) than 5-HTTLPR.

Dynamic brain sources of visual evoked responses.

It has been long debated whether averaged electrical responses recorded from the scalp result from stimulus-evoked brain events or stimulus-induced changes in ongoing brain dynamics. In a human visual selective attention task, we show that nontarget event-related potentials were mainly generated by partial stimulus-induced phase resetting of multiple electroencephalographic processes. Independent component analysis applied to the single-trial data identified at least eight classes of contributing components, including those producing central and lateral posterior alpha, left and right mu, and frontal midline theta rhythms. Scalp topographies of these components were consistent with their generation in compact cortical domains.

Relationship between head circumference and brain volume in healthy normal toddlers, children, and adults.

OBJECTIVE: To quantify the relationship between brain volume and head circumference from early childhood to adulthood, and quantify how this relationship changes with age. METHODS: Whole-brain volume and head circumference measures were obtained from MR images of 76 healthy normal males aged 1.7 to 42 years. RESULTS: Across early childhood, brain volume and head circumference both increase, but from adolescence onward brain volume decreases while head circumference does not. Because of such changing relationships between brain volume and head circumference with age, a given head circumference was associated with a wide range of brain volumes. However, when grouped appropriately by age, head circumference was shown to accurately predict brain volume. Head circumference was an excellent prediction of brain volume in 1.7 to 6 years old children (r = 0.93), but only an adequate predictor in 7 to 42 year olds. CONCLUSIONS: To use head circumference as an accurate indication of abnormal brain volume in the clinic or research setting, the patient's age must be taken into account. With knowledge of age-dependent head circumference-to-brain volume relationship, head circumference (particularly in young children) can be an accurate, rapid, and inexpensive indication of normalcy of brain size and growth in a clinical setting.

Face processing occurs outside the fusiform 'face area' in autism: evidence from functional MRI.

Processing the human face is at the focal point of most social interactions, yet this simple perceptual task is difficult for individuals with autism, a population that spends limited amounts of time engaged in face-to-face eye contact or social interactions in general. Thus, the study of face processing in autism is not only important because it may be integral to understanding the social deficits of this disorder, but also, because it provides a unique opportunity to study experiential factors related to the functional specialization of normal face processing. In short, autism may be one of the only disorders where affected individuals spend reduced amounts of time engaged in face processing from birth. Using functional MRI, haemodynamic responses during a face perception task were compared between adults with autism and normal control subjects. Four regions of interest (ROIs), the fusiform gyrus (FG), inferior temporal gyrus, middle temporal gyrus and amygdala were manually traced on non-spatially normalized images and the percentage ROI active was calculated for each subject. Analyses in Talairach space were also performed. Overall results revealed either abnormally weak or no activation in FG in autistic patients, as well as significantly reduced activation in the inferior occipital gyrus, superior temporal sulcus and amygdala. Anatomical abnormalities, in contrast, were present only in the amygdala in autistic patients, whose mean volume was significantly reduced as compared with normals. Reaction time and accuracy measures were not different between groups. Thus, while autistic subjects could perform the face perception task, none of the regions supporting face processing in normals were found to be significantly active in the autistic subjects. Instead, in every autistic patient, faces maximally activated aberrant and individual-specific neural sites (e.g. frontal cortex, primary visual cortex, etc.), which was in contrast to the 100% consistency of maximal activation within the traditional fusiform face area (FFA) for every normal subject. It appears that, as compared with normal individuals, autistic individuals 'see' faces utilizing different neural systems, with each patient doing so via a unique neural circuitry. Such a pattern of individual-specific, scattered activation seen in autistic patients in contrast to the highly consistent FG activation seen in normals, suggests that experiential factors do indeed play a role in the normal development of the FFA.

Analysis and visualization of single-trial event-related potentials.

In this study, a linear decomposition technique, independent component analysis (ICA), is applied to single-trial multichannel EEG data from event-related potential (ERP) experiments. Spatial filters derived by ICA blindly separate the input data into a sum of temporally independent and spatially fixed components arising from distinct or overlapping brain or extra-brain sources. Both the data and their decomposition are displayed using a new visualization tool, the "ERP image," that can clearly characterize single-trial variations in the amplitudes and latencies of evoked responses, particularly when sorted by a relevant behavioral or physiological variable. These tools were used to analyze data from a visual selective attention experiment on 28 control subjects plus 22 neurological patients whose EEG records were heavily contaminated with blink and other eye-movement artifacts. Results show that ICA can separate artifactual, stimulus-locked, response-locked, and non-event-related background EEG activities into separate components, a taxonomy not obtained from conventional signal averaging approaches. This method allows: (1) removal of pervasive artifacts of all types from single-trial EEG records, (2) identification and segregation of stimulus- and response-locked EEG components, (3) examination of differences in single-trial responses, and (4) separation of temporally distinct but spatially overlapping EEG oscillatory activities with distinct relationships to task events. The proposed methods also allow the interaction between ERPs and the ongoing EEG to be investigated directly. We studied the between-subject component stability of ICA decomposition of single-trial EEG epochs by clustering components with similar scalp maps and activation power spectra. Components accounting for blinks, eye movements, temporal muscle activity, event-related potentials, and event-modulated alpha activities were largely replicated across subjects. Applying ICA and ERP image visualization to the analysis of sets of single trials from event-related EEG (or MEG) experiments can increase the information available from ERP (or ERF) data.

Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study.

OBJECTIVE: To quantify developmental abnormalities in cerebral and cerebellar volume in autism. METHODS: The authors studied 60 autistic and 52 normal boys (age, 2 to 16 years) using MRI. Thirty autistic boys were diagnosed and scanned when 5 years or older. The other 30 were scanned when 2 through 4 years of age and then diagnosed with autism at least 2.5 years later, at an age when the diagnosis of autism is more reliable. RESULTS: Neonatal head circumferences from clinical records were available for 14 of 15 autistic 2- to 5-year-olds and, on average, were normal (35.1 +/- 1.3 cm versus clinical norms: 34.6 +/- 1.6 cm), indicative of normal overall brain volume at birth; one measure was above the 95th percentile. By ages 2 to 4 years, 90% of autistic boys had a brain volume larger than normal average, and 37% met criteria for developmental macrencephaly. Autistic 2- to 3-year-olds had more cerebral (18%) and cerebellar (39%) white matter, and more cerebral cortical gray matter (12%) than normal, whereas older autistic children and adolescents did not have such enlarged gray and white matter volumes. In the cerebellum, autistic boys had less gray matter, smaller ratio of gray to white matter, and smaller vermis lobules VI-VII than normal controls. CONCLUSIONS: Abnormal regulation of brain growth in autism results in early overgrowth followed by abnormally slowed growth. Hyperplasia was present in cerebral gray matter and cerebral and cerebellar white matter in early life in patients with autism.

Development of the hippocampal formation from 2 to 42 years: MRI evidence of smaller area dentata in autism.

Autism, a neuropsychiatric disorder that severely impairs social, language and cognitive development, has a clinical onset in the first years of life. Because components of the limbic system mediate memory, social and affective functions that are typically disturbed in autism, a developmental defect in the limbic system has been hypothesized to underlie different autistic symptoms, but no developmental study has been performed. To obtain neuroanatomical evidence of limbic system abnormality in autism, we measured the cross-sectional area of the area dentata (AD; dentate gyrus + CA4) and combined area of the subiculum and CA1-CA3 (CAS) using in vivo MRI. Autistic patients aged 29 months to 42 years (n = 59) and healthy normal controls (n = 51) participated. The cross-sectional area of the AD was significantly smaller than normal in autism, the largest deviation from normal size (-13.5%) being found in autistic children aged 29 months to 4 years. Strong age-related increases were seen in the cross-sectional area of CAS, but autistic and normal subjects were not significantly different. This is the first direct evidence that anatomical abnormality within the limbic system exists from the earliest years of the disorder, and persists throughout development and to middle age.