BrainForge: an online data analysis platform for integrative neuroimaging acquisition, analysis, and sharing.

BrainForge is a cloud-enabled, web-based analysis platform for neuroimaging research. This website allows users to archive data from a study and effortlessly process data on a high-performance computing cluster. After analyses are completed, results can be quickly shared with colleagues. BrainForge solves multiple problems for researchers who want to analyze neuroimaging data, including issues related to software, reproducibility, computational resources, and data sharing. BrainForge can currently process structural, functional, diffusion, and arterial spin labeling MRI modalities, including preprocessing and group level analyses. Additional pipelines are currently being added, and the pipelines can accept the BIDS format. Analyses are conducted completely inside of Singularity containers and utilize popular software packages including Nipype, Statistical Parametric Mapping, the Group ICA of fMRI Toolbox, and FreeSurfer. BrainForge also features several interfaces for group analysis, including a fully automated adaptive ICA approach.

1H-MRS glutamate level predicts auditory sensory gating in alcohol dependence: Preliminary results.

BACKGROUND: Impairment in auditory sensory gating (ASG) has been documented in alcohol dependence [1]. Likewise, it has been shown that ASG becomes abnormal during alcohol administration in otherwise healthy individuals [2]. Patterns of gating abnormality associated with alcohol use are likely associated with an alcohol responsive neurochemical like glutamate (Glu), particularly since it is well-established that alcohol affects NMDA receptors and that glutamatergic functioning is abnormal in both acute alcohol use and in alcohol dependence [3]. Hence, a link between Glu metabolite levels and ASG was hypothesized. It was first hypothesized that Glu and ASG abnormality would be found in groups with alcohol dependence. A second hypothesis was that across groups, greater Glu would predict reduced ASG. METHODS: Groups were comprised of healthy, non-drinking controls (Controls, N = 4), individuals with current alcohol dependence (AUD-current, N = 6), and with alcohol dependence in remission for at least 1 year (AUD-remission, N = 6). Participants underwent a diagnostic assessment for alcohol consumption, MRI, 1H-MRS for in vivo assessment of Glu and other metabolites, and MEG scanning during a paired click protocol. ASG was computed as the ratio of the source strength of the 50 ms component in the event related field (ERF) to the second click in the pair divided by the source strength of the 50 ms component to the first click in the pair. RESULTS: Univariate MANOVAs controlling for age and gender revealed a significant effect for group on Glu and ASG, such that ASG ratios were significantly elevated, implying weakened gating. Glu concentration was reduced in AUD-current relative to the other two groups. Further analysis revealed that when additionally controlling for the group effect, reduced Glu predicted increasing impairment in ASG. CONCLUSIONS: The overall results were consistent with the hypothesis that differences in Glu metabolite levels associated with alcohol dependence result in impaired ASG.

Proton magnetic resonance spectroscopy and MRI reveal no evidence for brain mitochondrial dysfunction in children with autism spectrum disorder.

Brain mitochondrial dysfunction has been proposed as an etiologic factor in autism spectrum disorder (ASD). Proton magnetic resonance spectroscopic imaging ((1)HMRS) and MRI were used to assess for evidence of brain mitochondrial dysfunction in longitudinal samples of children with ASD or developmental delay (DD), and cross-sectionally in typically developing (TD) children at 3-4, 6-7 and 9-10 years-of-age. A total of 239 studies from 130 unique participants (54ASD, 22DD, 54TD) were acquired. (1)HMRS and MRI revealed no evidence for brain mitochondrial dysfunction in the children with ASD. Findings do not support a substantive role for brain mitochondrial abnormalities in the etiology or symptom expression of ASD, nor the widespread use of hyperbaric oxygen treatment that has been advocated on the basis of this proposed relationship.

Improving 1H MRSI measurement of cerebral lactate for clinical applications.

Accurate measurement of cerebral lactate is critical to the understanding of brain function for psychiatric disorders such as panic disorder and bipolar disorder as well as mitochondrial dysfunction. Proton magnetic spectroscopic imaging (MRSI) techniques can be used to study lactate in vivo; however, accurate measurement of cerebral lactate, which is normally at low basal abundance, can be challenging. In this study, regional lactate measurements obtained with two different MRSI analytic approaches were evaluated using proton echo-planar spectroscopic imaging (PEPSI) data from 18 healthy adults participating in an in vivo sodium lactate infusion study. The results demonstrate that averaging data within a region of interest (ROI) before spectral fitting with LCModel results in significantly improved lactate measurement as compared to averaging chemical concentrations derived from the fitting of individual voxels in the ROI. Simulation results that confirm this finding are also presented. This study additionally outlines an atlas-based approach for the systematic computation of regional distributions of chemical concentrations in large MRSI data sets.

Hippocampus volume and episodic memory in schizophrenia.

Previous studies of schizophrenia have suggested a linkage between neuropsychological (NP) deficits and hippocampus abnormality. The relationship between hippocampus volume and NP functioning was investigated in 24 patients with chronic schizophrenia and 24 matched healthy controls. Overall intracranial, white and gray matter, and anterior (AH) and posterior (PH) hippocampus volumes were assessed from magnetic resonance images (MRI). NP domains of IQ, attention, and executive function were also evaluated with respect to volumetric measures. It was hypothesized that AH and PH volumes and episodic memory scores would be positively associated in controls and that the schizophrenia group would depart from this normative pattern. NP functioning was impaired overall and AH volume was smaller in the schizophrenia group. In the controls, the hippocampus-memory relationships involved AH and PH, and correlations were significant for verbal memory measures. In the schizophrenia group, positive correlations were constrained to PH. Negative correlations emerged between AH and verbal and visual memory measures. For both groups, cortical volume negatively correlated with age, but a negative correlation between age and hippocampus volume was found only in the schizophrenia group. In this sample of adults with schizophrenia, atypical relationships between regional hippocampus volumes and episodic memory ability were found, as was an atypical negative association between hippocampus volume and age.

Schizophrenia diagnosis and anterior hippocampal volume make separate contributions to sensory gating.

Impaired P50 gating is thought to reflect a core deficit in schizophrenia, but the relevant neural network is not well understood. The present study used EEG and MEG to assess sensory gating and volumetric MRI to measure hippocampal volume to investigate relationships between them in 22 normal controls and 22 patients with schizophrenia. In the schizophrenia group, anterior but not posterior hippocampal volume was smaller, and both the P50 and M50 gating ratios were larger (worse) than in controls. Independent of group, left-hemisphere M50 gating ratio correlated negatively with left anterior hippocampal volume, and right-hemisphere M50 gating ratio correlated negatively with right anterior hippocampal volume. Schizophrenia diagnosis predicted M50 gating independent of hippocampal volume. These results are consistent with the finding that hippocampus is a critical part of a fronto-temporal circuit involved in auditory gating.

Gray and white matter brain chemistry in young children with autism.

CONTEXT: The brain pathophysiological abnormalities underlying autism remain unclear. Neuroimaging and histological studies suggest cellular abnormalities early in the course of the disease. OBJECTIVE: To measure the in vivo chemical profile of gray and white matter tissues in autism. DESIGN: Cross-sectional spectroscopic imaging study comparing 3- to 4-year-old children with autism spectrum disorder (ASD) with age-matched comparison groups of children with delayed development (DD) and typical development (TD). SETTING: The University of Washington Diagnostic Imaging Sciences Center, Seattle. PARTICIPANTS: Forty-five 3- to 4-year-old children with ASD, 12 age-matched children with DD, and 10 age-matched children with TD. MAIN OUTCOME MEASURES: Estimates of gray and white matter concentrations for choline-containing compounds (Cho), creatine plus phosphocreatine, N-acetylaspartate (NAA), and myo-inositol (mI). Transverse relaxation times for Cho, creatine plus phosphocreatine, and NAA expressed relative to control subjects with TD were examined to evaluate tissue compactness. RESULTS: The children with ASD demonstrated decreased gray matter concentrations of Cho (P < .001), creatine plus phosphocreatine (P = .02), NAA (P = .02), and mI (P = .008) compared with children with TD. Gray matter Cho transverse relaxation was also prolonged for the ASD sample compared with the TD group (P = .01). The children with ASD demonstrated significantly decreased levels of Cho (P = .04) and mI (P = .008) and trend-level NAA (P = .09) in gray matter compared with the DD group. For white matter, both children with ASD and children with DD showed a similar pattern of NAA and mI level decreases (for children with ASD vs children with TD: NAA, P = .03; mI, P = .04; for children with DD vs children with TD, NAA, P = .03; mI, P = .07). In several analyses, cerebral volume contributed significantly as a covariate. CONCLUSIONS: Reduced gray matter chemical concentrations and altered Cho transverse relaxation, in a pattern distinct from that in children with DD, suggest decreased cellularity, or density, at this early time point in ASD. Possibly reflecting shared developmental features, white matter results were common to ASD and DD groups. The relationship between cerebral volume and neurochemistry at this early time point may indicate processes related to unit scaling.

Sex differences in N-acetylaspartate correlates of general intelligence: an 1H-MRS study of normal human brain.

Researchers have long attempted to determine brain correlates of intelligence using available neuroimaging technology including CT, MRI, PET, and fMRI. Although structural and functional imaging techniques are well suited to assess gross cortical regions associated with intelligence, the integrity and functioning of underlying white matter networks critical to coordinated cortical integration remain comparatively understudied. A relatively recent neuroimaging advance is magnetic resonance spectroscopy (MRS) which allows for interrogation of biochemical substrates of brain structure and function in vivo. In this study, we examined twenty-seven normal control subjects (17 male, 10 female) to determine whether N-acetylaspartate (NAA), a metabolite found primarily within neurons, is related to intelligence as assessed by the Wechsler Adult Intelligence Scale-III. Of the three white matter regions studied (i.e., left frontal, right frontal, left occipito-parietal), we found that a model including only left occipito-parietal white matter predicted intellectual performance [F(1,25) = 8.65, P = .007; r2 = .26], providing regional specificity to our previous findings of NAA-IQ relationships. Moreover, we found that a complex combination of left frontal and left occipito-parietal NAA strongly predicted performance in women, but not men [F(2,7) = 21.84, P < .001; adjusted r2 = .82]. Our results highlight a biochemical substrate of normal intellectual performance, mediated by sex, within white matter association fibers linking posterior to frontal brain regions.

Multisequence magnetic resonance imaging study of neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To investigate the relationship between magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), proton magnetic resonance spectroscopy (H-MRS), and T2 relaxometry findings in patients with primary neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: The study group consisted of 24 female patients (mean age 36 years [range 23-65]) who had had a variety of neuropsychiatric symptoms that were judged to be due to NPSLE according to the criteria of the American College of Rheumatology. Patients with current active disease were excluded from participation. Quantitative MTI, DWI, H-MRS, and T2 relaxometry data were acquired in all patients, and the correlation coefficients were calculated. RESULTS: MTI results reflecting a decrease in homogeneity of cerebral parenchyma correlated significantly with H-MRS results representing axonal damage. MTI results also correlated significantly with DWI results reflecting increased diffusivity in the cerebral parenchyma. Finally, MTI results reflecting decreased cerebral homogeneity correlated significantly with increased T2 relaxation time, associated with either edema or gliosis. Increased T2 relaxation time correlated significantly with DWI results reflecting increased diffusivity. With the exception of the correlation between H-MRS and MTI findings, there was no significant correlation between H-MRS results and any other parameter. CONCLUSION: The selected study parameters represent different biologic features in the human brain and can be informative with regard to different pathologic processes in NPSLE. The demonstrated associations between MTI, DWI, H-MRS, and T2 data in patients with a history of NPSLE suggest that there is one pathogenesis and/or common neuropathologic outcome in NPSLE despite differences in clinical presentation.

Reduced area of the corpus callosum in posttraumatic stress disorder.

Magnetic resonance imaging (MRI) studies have revealed decreases in the mid-sagittal area of the corpus callosum (CC) in pediatric posttraumatic stress disorder (PTSD), but at present no data are available in adult PTSD patients. We have previously reported decreased whole-brain white matter (WM) volume in adults with PTSD and now report corpus callosum area from the same sample. MRI was used to obtain whole-brain images in 12 adult patients with PTSD and 10 matched controls. Total parenchyma (white matter plus gray matter [GM]) volume, mid-sagittal area of the CC and seven sub-regions of this structure were calculated. In PTSD patients, the total CC area, absolute and normalized to total brain parenchyma, was smaller compared with control values. Several absolute and normalized CC sub-regions were also smaller in PTSD patients: genu (region 2), mid-body (region 5) and isthmus (region 6). There was also a trend for the anterior mid-body (area 4) to be smaller in PTSD patients. No differences were found in the rostrum (region 1), rostral body (region 3) or splenium (region 7). Adult patients with PTSD had decreased CC area after correcting for total brain tissue, indicating that these differences are not attributable to generalized white matter atrophy. These findings are similar to previous results in children with PTSD and suggest specific changes in the CC.

Disruption of Meox or Gli activity ablates skeletal myogenesis in P19 cells.

Gli2 and Meox1 are transcription factors that are expressed in the developing somite and play roles in the commitment of cells to the skeletal muscle lineage. To further define their roles in regulating myogenesis, the function of wild type and dominant-negative forms of Gli2 and Meox1 were examined in the context of differentiating P19 stem cells. We found that Gli2 overexpression up-regulated transcript levels of Meox1 and, conversely, Meox1 overexpression resulted in the upregulation of Gli2 transcripts. Furthermore, dominant-negative forms of either Meox1 or Gli2 disrupted the ability of P19 cells to commit to the muscle lineage and to properly express either Gli2 or Meox1, respectively. Finally, Pax3 transcripts were induced by Gli2 overexpression and lost in the presence of either mutants Meox1 or Gli2. Taken together, these results support the existence of a regulatory loop between Gli2, Meox1, and Pax3 that is essential for specification of mesodermal cells into the muscle lineage.

The aging hippocampus: cognitive, biochemical and structural findings.

Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippocampus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cognition in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippocampal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collectively, our results suggest that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampus-dependent cognition.

Proton magnetic resonance spectroscopy investigation of the right frontal lobe in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To investigate neurometabolite concentrations in right prefrontal white matter in children with attention-deficit/hyperactivity disorder (ADHD) and relations of neurometabolites with attention skill and frontal anatomy. METHOD: Single voxel proton magnetic resonance spectroscopy ( H-MRS), quantitative morphometric analysis of left and right dorsolateral frontal volumes, and assessment of attentional problems with the Conners Continuous Performance Test were undertaken in 23 children (17 male) with ADHD (with no comorbid learning disabilities) and 24 matched controls (16 male). RESULTS: No overall group differences were found for any neurometabolite. However, a group by sex interaction was noted for -acetylaspartate, such that girls with ADHD had especially low concentrations. Morphological analyses revealed smaller right (but not left) dorsolateral volumes in children with ADHD, and in the ADHD group this volume correlated with neurometabolite concentrations. In the ADHD group Continuous Performance Test performance was related to both dorsolateral volume and the creatine-phosphocreatine peak from H-MRS. CONCLUSIONS: These results add to a growing body of evidence suggesting sex-specific neurobiological differences in ADHD and draw attention to relationships between neurochemistry, neuroanatomy, and performance in children with ADHD. Study limitations include small sample size and clinical heterogeneity among the children with ADHD.

Longitudinal follow-up of neurochemical changes during the first year of antipsychotic treatment in schizophrenia patients with minimal previous medication exposure.

Reduced frontal N-acetylaspartate (NAA) has been repeatedly found in chronic schizophrenia and suggests neuronal loss or dysfunction. However, the potential confounding effect of antipsychotic drugs on NAA has not been resolved. The few studies of antipsychotic-nai;ve patients are inconclusive. A recent report suggests that antipsychotic drugs may increase NAA in the dorsolateral prefrontal cortex (DLPFC). We studied 10 minimally treated (less than 3 weeks lifetime exposure) schizophrenia patients and 10 normal controls with single-voxel proton magnetic resonance spectroscopy (1H-MRS) of the left frontal and occipital lobes. Concentrations of NAA, Cho, and Cre were determined and corrected for the proportion of cerebrospinal fluid (CSF) in the voxel. Patients were treated in a randomized-controlled double-blind design with either haloperidol or quetiapine. 1H-MRS was repeated within a year. There were no differences in frontal or occipital NAA between patients and controls at baseline. However, frontal NAA was reduced in the schizophrenia group within the first year of treatment. Patients had a clear clinical response to treatment but changes in frontal NAA were not correlated with symptom improvement. The well-described reduced frontal NAA in schizophrenia may not be a trait of the illness but may represent medication effect or progression of the disease.

Proton magnetic resonance spectroscopy of the hippocampus and occipital white matter in PTSD: preliminary results.

OBJECTIVE: Previous proton magnetic resonance spectroscopy (1H-MRS) studies in posttraumatic stress disorder (PTSD) report decreased hippocampal N-acetylaspartate (NAA), an indicator of neuronal integrity. However, other areas of the brain need to be explored. The objective of this study was to investigate the specificity of hippocampal NAA concentration changes in PTSD by also examining a control region, the occipital white matter (OWM). METHODS: Eight patients with PTSD and 5 control subjects underwent single-voxel 1H-MRS of the hippocampi and bilateral OWM. Absolute neurometabolite concentrations were determined. PRELIMINARY RESULTS: Trends toward reduced left hippocampal NAA and creatine (Cre) were found in the PTSD group. PTSD subjects also had reduced bilateral OWM Cre. CONCLUSIONS: The preliminary results of our study in civilians with PTSD replicate previous MRS studies and are consistent with decreased hippocampal neuronal integrity without effects in the OWM. Replication of our findings is needed.

Reduced hippocampal volume and total white matter volume in posttraumatic stress disorder.

BACKGROUND: Reduced hippocampal volumes in posttraumatic stress disorder (PTSD) patients are thought to reflect specific changes of this structure. Previous magnetic resonance imaging (MRI) studies have not consistently examined indices of overall brain atrophy, therefore it cannot be completely ruled out that hippocampal changes are explained by whole-brain atrophy. The purpose of this study was to assess hippocampal and whole-brain volume in civilian PTSD. METHODS: Twelve subjects with PTSD and 10 control subjects underwent brain MRI. Hippocampal volumes were visually quantified using a computerized volumetric program. Whole-brain volumes were obtained with automated k-means-based segmentation. RESULTS: No differences were found in intracranial volumes (ICV). Subjects with PTSD had higher cerebrospinal fluid (CSF)/ICV ratios and lower white matter/ICV ratios, consistent with generalized white matter (WM) atrophy. The effect of age on CSF/ICV was more pronounced in the PTSD group. Subjects with PTSD had smaller absolute and normalized bilateral hippocampal volumes. These differences persisted after adjusting for lifetime weeks of alcohol intoxication. Posttraumatic stress disorder and depression scores correlated negatively with left hippocampal volume, but PTSD scores were a better predictor of hippocampal volumes. CONCLUSIONS: Our results replicate previous findings of reduced hippocampal volume in PTSD but also suggest independent, generalized, white matter atrophy.

The E2 ubiquitin conjugase Rad6 is required for the ArgR/Mcm1 repression of ARG1 transcription.

Transcription of the Saccharomyces cerevisiae ARG1 gene is under the control of both positive and negative elements. Activation of the gene in minimal medium is induced by Gcn4. Repression occurs in the presence of arginine and requires the ArgR/Mcm1 complex that binds to two upstream arginine control (ARC) elements. With the recent finding that the E2 ubiquitin conjugase Rad6 modifies histone H2B, we examined the role of Rad6 in the regulation of ARG1 transcription. We find that Rad6 is required for repression of ARG1 in rich medium, with expression increased approximately 10-fold in a rad6 null background. Chromatin immunoprecipitation analysis indicates increased binding of TATA-binding protein in the absence of Rad6. The active-site cysteine of Rad6 is required for repression, implicating ubiquitination in the process. The effects of Rad6 at ARG1 involve two components. In one of these, histone H2B is the likely target for ubiquitination by Rad6, since a strain expressing histone H2B with the principal ubiquitination site converted from lysine to arginine shows a fivefold relief of repression. The second component requires Ubr1 and thus likely the pathway of N-end rule degradation. Through the analysis of promoter constructs with ARC deleted and an arg80 rad6 double mutant, we show that Rad6 repression is mediated through the ArgR/Mcm1 complex. In addition, analysis of an ada2 rad6 deletion strain indicated that the SAGA acetyltransferase complex and Rad6 act in the same pathway to repress ARG1 in rich medium.

Beta-catenin is essential and sufficient for skeletal myogenesis in P19 cells.

Wnt1 and Wnt3a are signaling factors known to play a role in the induction of myogenesis in the myotome of the differentiating somite. Both factors may transduce their signal by a conserved pathway that leads to transcriptional regulation by beta-catenin/Lef1. beta-Catenin and Lef1 are found in the myotome prior to MyoD expression. We have utilized the P19 cell system to study the mechanisms by which Wnt3a may activate MyoD expression and subsequent skeletal muscle development. We have isolated P19 cell lines that stably express either Wnt3a or activated beta-catenin and found that aggregation of these cells results in the induction of myogenesis compared with control cells. Pax3, Gli2, Mox1, and Six1 were expressed during Wnt3a and beta-catenin-induced differentiation prior to MyoD expression. Furthermore, we have shown that the nuclear function of beta-catenin was essential for skeletal myogenesis in P19 cells by overexpression of a dominant negative beta-catenin/engrailed chimera. Primitive streak factors were present, but expression of Pax3, Mox1, Gli2, and Six1 was lost in these cells, indicating that nuclear beta-catenin is essential for specification of mesodermal precursors to the myogenic lineage. Therefore, Wnt signaling, acting via beta-catenin, is necessary and sufficient for skeletal myogenesis in P19 cells.

Biochemical markers of mood: a proton magnetic resonance spectroscopy study of normal human brain.

BACKGROUND: Elevated brain Cho has been shown within the basal ganglia and frontal (i.e., orbitofrontal and cingulate) cortices in patients with mood disorders utilizing Proton Magnetic Resonance Spectroscopy (1H-MRS). We sought to determine the relationship between Cho and mood in a cohort of healthy young subjects. METHODS: Twenty-seven subjects without neurologic or psychiatric disorders were evaluated with the Positive and Negative Affect Scale and underwent 1H-MRS of bilateral frontal and occipito-parietal white matter. RESULTS: We found that Cho in the left frontal lobe was inversely correlated with Positive Affect [F(1,24) = 19.2, p <.001, r(2) =.45]. CONCLUSIONS: Our results highlight the important involvement of Cho underlying the integration of affective processing within prefrontal circuitry, and may indicate increased myelin turnover in subjects with lower Positive Affect. Further efforts will be necessary to determine if high Cho is associated with increased incidence of mood disorders throughout life.

High choline concentrations in the caudate nucleus in antipsychotic-naive patients with schizophrenia.

OBJECTIVE: Proton magnetic resonance spectroscopy ((1)H-MRS) studies of medicated patients with schizophrenia suggest high choline levels in the caudate nucleus. However, assessments of antipsychotic-naive patients are needed. METHOD: The authors studied 11 antipsychotic-naive schizophrenia patients and 11 normal comparison subjects with single-voxel (1)H-MRS of the left caudate nucleus. Concentrations of N-acetylaspartate, choline, and creatine were determined and corrected for the proportion of cerebrospinal fluid in the voxel. RESULTS: The patients with schizophrenia had significantly higher levels of choline than the comparison subjects, while the other two metabolites did not differ between groups. CONCLUSIONS: High caudate choline levels in schizophrenia are not secondary to antipsychotic treatment.