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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 trajectories2of 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.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Despite decades of research, the pathophysiology of bipolar disorder (BD) is still not well understood. Structural brain differences have been associated with BD, but results from neuroimaging studies have been inconsistent. To address this, we performed the largest study to date of cortical gray matter thickness and surface area measures from brain magnetic resonance imaging scans of 6503 individuals including 1837 unrelated adults with BD and 2582 unrelated healthy controls for group differences while also examining the effects of commonly prescribed medications, age of illness onset, history of psychosis, mood state, age and sex differences on cortical regions. In BD, cortical gray matter was thinner in frontal, temporal and parietal regions of both brain hemispheres. BD had the strongest effects on left pars opercularis (Cohen’s d=-0.293; P=1.71 × 10-21), left fusiform gyrus (d=-0.288; P=8.25 × 10-21) and left rostral middle frontal cortex (d=-0.276; P=2.99 × 10-19). Longer duration of illness (after accounting for age at the time of scanning) was associated with reduced cortical thickness in frontal, medial parietal and occipital regions. We found that several commonly prescribed medications, including lithium, antiepileptic and antipsychotic treatment showed significant associations with cortical thickness and surface area, even after accounting for patients who received multiple medications. We found evidence of reduced cortical surface area associated with a history of psychosis but no associations with mood state at the time of scanning. Our analysis revealed previously undetected associations and provides an extensive analysis of potential confounding variables in neuroimaging studies of BD.

Clozapine is one of the most effective atypical antipsychotic drugs prescribed to patients with treatment-resistant schizophrenia. Approximately 1% of patients experience potential life-threatening adverse effects in the form of agranulocytosis, greatly hindering its applicability in clinical practice. The etiology of clozapine-induced agranulocytosis (CIA) remains unclear, but is thought to be a heritable trait. We reviewed the genetic studies of CIA published thus far. One recurrent finding from early candidate gene study to more recent genome-wide analysis is that of the involvement of human leukocyte antigen locus. We conclude that CIA is most likely a complex, polygenic trait, which may hamper efforts to the development of a genetic predictor test with clinical relevance. To decipher the genetic architecture of CIA, it is necessary to apply more rigorous standards of phenotyping and study much larger sample sizes.

Considerable uncertainty exists about the defining brain changes associated with bipolar disorder (BD). Understanding and quantifying the sources of uncertainty can help generate novel clinical hypotheses about etiology and assist in the development of biomarkers for indexing disease progression and prognosis. Here we were interested in quantifying case–control differences in intracranial volume (ICV) and each of eight subcortical brain measures: nucleus accumbens, amygdala, caudate, hippocampus, globus pallidus, putamen, thalamus, lateral ventricles. In a large study of 1710 BD patients and 2594 healthy controls, we found consistent volumetric reductions in BD patients for mean hippocampus (Cohen’s d=−0.232; P=3.50 × 10−7) and thalamus (d=−0.148; P=4.27 × 10−3) and enlarged lateral ventricles (d=−0.260; P=3.93 × 10−5) in patients. No significant effect of age at illness onset was detected. Stratifying patients based on clinical subtype (BD type I or type II) revealed that BDI patients had significantly larger lateral ventricles and smaller hippocampus and amygdala than controls. However, when comparing BDI and BDII patients directly, we did not detect any significant differences in brain volume. This likely represents similar etiology between BD subtype classifications. Exploratory analyses revealed significantly larger thalamic volumes in patients taking lithium compared with patients not taking lithium. We detected no significant differences between BDII patients and controls in the largest such comparison to date. Findings in this study should be interpreted with caution and with careful consideration of the limitations inherent to meta-analyzed neuroimaging comparisons.

The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen’s d=−0.46), amygdala (d=−0.31), thalamus (d=−0.31), accumbens (d=−0.25) and intracranial volumes (d=−0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

What determines how well an individual can manage the complexity of information processing demands when several tasks have to be executed simultaneously? Various theoretical frameworks address the mechanisms of information processing and the changes that take place when processes become automated, and brain regions involved in various types of information processing have been identified, as well as sequences of events in the brain. The neurophysiological substrate of human information processing capacity, i.e. the amount that can be processed simultaneously, is, however, unresolved, as is the basis of inter‐individual variability in capacity. Automatization of cognitive functions is known to increase capacity to process additional tasks, but behavioural indices of automatization are poor predictors of processing capacity in individuals. Automatization also leads to a decline of brain activity in the working memory system. In this study, we test the hypothesis that processing capacity is closely related to the way that the brain adjusts to practice of a single cognitive task, i.e. to the changes in neuronal activity that accompany automatization as measured with functional MRI (fMRI). Using a task that taxes the working memory system, and is sensitive to automatization, performance improved while activity in the network declined, as expected. The key finding is that the magnitude of automatization‐induced reduction of activity in this system was a strong predictor for the ability to perform two different working memory tasks simultaneously (after scanning). It explained 60% of the variation in information processing capacity across individuals. In contrast, the behavioural measures of automatization did not predict this. We postulate that automatization involves at least two partially independent neurophysiological mechanisms, i.e. (i) streamlining of neuronal communication which improves performance on a single task; and (ii) functional trimming of neuronal ensembles which enhances the capacity to accommodate processing of additional tasks, potentially by facilitating rapid switching of instruction sets or contexts. Finally, this study shows that fMRI can provide information that predicts behavioural output, which is not provided by overt behavioural measures.

An unexpectedly high percentage of monozygotic twin pairs is discordant for handedness. Some of these twins show mirror‐imaging of several ectodermally derived features. Both features of discordant left–right asymmetry may be caused by relatively late monozygotic twinning, when the original embryo has already lost its bilateral symmetry. Language lateralization is related to handedness and may therefore also be altered during the development of embryological asymmetry in some monozygotic twins. Language lateralization was measured with functional MRI in 12 monozygotic twin pairs who were concordant for handedness and in 13 monozygotic twin pairs discordant for handedness. Lateralization indices were calculated from indi vidual language activation patterns. Correlations were calculated to test intra‐pair resemblance for language lateralization. The intra‐pair correlation for language lateralization was significant in the handedness‐concordant group, but not in the handedness‐discordant group. In the handedness‐discordant group, five twin pairs were also discordant for cerebral dominance; the other twin pairs of discordant handedness exhibited remarkable similarity in language lateralization. The high intra‐pair correlation for language lateralization in the handedness‐concordant twins suggests a genetic basis for language lateralization. However, in monozygotic twin pairs of discordant handedness, discordance for language dominance occurs in a significant number of twins. Discordant language dominance may be caused by a relatively late time of splitting of the original embryo, which disrupts the normal development of left–right asymmetry.

An unexpectedly high percentage of monozygotic twin pairs is discordant for handedness. Some of these twins show mirror-imaging of several ectodermally derived features. Both features of discordant left-right asymmetry may be caused by relatively late monozygotic twinning, when the original embryo has already lost its bilateral symmetry. Language lateralization is related to handedness and may therefore also be altered during the development of embryological asymmetry in some monozygotic twins. Language lateralization was measured with functional MRI in 12 monozygotic twin pairs who were concordant for handedness and in 13 monozygotic twin pairs discordant for handedness. Lateralization indices were calculated from individual language activation patterns. Correlations were calculated to test intra-pair resemblance for language lateralization. The intra-pair correlation for language lateralization was significant in the handedness-concordant group, but not in the handedness-discordant group. In the handedness-discordant group, five twin pairs were also discordant for cerebral dominance; the other twin pairs of discordant handedness exhibited remarkable similarity in language lateralization. The high intra-pair correlation for language lateralization in the handedness-concordant twins suggests a genetic basis for language lateralization. However, in monozygotic twin pairs of discordant handedness, discordance for language dominance occurs in a significant number of twins. Discordant language dominance may be caused by a relatively late time of splitting of the original embryo, which disrupts the normal development of left-right asymmetry.

Schizophrenic patients generally perform poorly on tasks that address executive functions. According to several imaging studies, the dorsolateral prefrontal cortex is hypoactive in schizophrenic patients during these tasks. It is not, however, clear whether this finding is associated more with impaired performance than with the illness itself, as performance has not been taken into account. We examined brain activity associated with executive function in schizophrenia using an experimental fMRI design that reveals performance effects, enabling correction for performance differences between groups. As this approach has not been reported before, and because brain function can be affected by medication, the effect of antipsychotic medication was also investigated. A task was used that requires logical reasoning, alongside a closely matched control task. Performance was accounted for by including individual responses in fMRI image analyses, as well as in group‐wise analysis. Effects of medication were addressed by comparing medication‐naïve patients and patients on atypical antipsychotic medication with healthy controls in two separate experiments. Imaging data were analysed with a novel, performance‐driven method, but also with a method that is similar to that used in earlier studies, which reported hypofrontality. A modest reduction in performance was found in both patient groups. Brain activity associated with logical reasoning was correlated positively with performance in all groups. In patients on medication, activity did not differ from that in controls after correcting for difference in performance. In contrast, performance‐corrected activity was significantly elevated in medication‐naïve patients. This study indicates that schizophrenia may be associated with excessive recruitment of brain systems during logical reasoning. Considering the fact that performance was reduced in the patients, we argue that the efficiency of neural communication may be affected by the illness. It appears that in patients on atypical antipsychotic medication, this neural inefficiency is normalized. The study shows that performance is an important factor in the interpretation of differences between schizophrenic patients and controls. The reported association between performance and brain activity is relevant to clinical imaging studies in general.

Schizophrenic patients generally perform poorly on tasks that address executive functions. According to several imaging studies, the dorsolateral prefrontal cortex is hypoactive in schizophrenic patients during these tasks. It is not, however, clear whether this finding is associated more with impaired performance than with the illness itself, as performance has not been taken into account. We examined brain activity associated with executive function in schizophrenia using an experimental fMRI design that reveals performance effects, enabling correction for performance differences between groups. As this approach has not been reported before, and because brain function can be affected by medication, the effect of antipsychotic medication was also investigated. A task was used that requires logical reasoning, alongside a closely matched control task. Performance was accounted for by including individual responses in fMRI image analyses, as well as in group-wise analysis. Effects of medication were addressed by comparing medication-naïve patients and patients on atypical antipsychotic medication with healthy controls in two separate experiments. Imaging data were analysed with a novel, performance-driven method, but also with a method that is similar to that used in earlier studies, which reported hypofrontality. A modest reduction in performance was found in both patient groups. Brain activity associated with logical reasoning was correlated positively with performance in all groups. In patients on medication, activity did not differ from that in controls after correcting for difference in performance. In contrast, performance-corrected activity was significantly elevated in medication-naïve patients. This study indicates that schizophrenia may be associated with excessive recruitment of brain systems during logical reasoning. Considering the fact that performance was reduced in the patients, we argue that the efficiency of neural communication may be affected by the illness. It appears that in patients on atypical antipsychotic medication, this neural inefficiency is normalized. The study shows that performance is an important factor in the interpretation of differences between schizophrenic patients and controls. The reported association between performance and brain activity is relevant to clinical imaging studies in general.

The effects of D-cycloserine, a partial agonist of the N-Methyl-D-Aspartate (NMDA) receptor, were assessed in a (neuroendocrine) challenge paradigm to examine NMDA systems in male healthy volunteers, using a double-blind, placebo-controlled crossover design. Oral D-cycloserine (15, 50, and 150 mg) was readily absorbed and its plasma concentration increased dose-dependently. Behavioral and hormonal responses were measured for 240 minutes after administration of the drug. D-cycloserine was well tolerated and did not induce side-effects according to the Visual Analog Scales (VAS), the Brief Psychiatric Rating Scale (BPRS) and the Adverse Events Checklist (AEC) & codes. D-cycloserine failed to elicit a neuroendocrine response as evaluated by cortisol, prolactin, and luteinizing hormone (LH) plasma levels. The present result suggests that D-cycloserine can readily be administered to healthy volunteers but that, in the dosages used, neuroendocrine secretion fails to serve as a model for testing NMDA receptor function in humans.

Correction to: Molecular Psychiatry (2015); advance online publication 2 June 2015; doi:10.1038/mp.2015.63 Following publication of the above article, the authors noticed that the forty-third author’s last name was presented incorrectly. The author’s name should have been listed as HE Hulshoff Pol. The publisher regrets the error.