Predictive Big Data Analytics using the UK Biobank Data.

The UK Biobank is a rich national health resource that provides enormous opportunities for international researchers to examine, model, and analyze census-like multisource healthcare data. The archive presents several challenges related to aggregation and harmonization of complex data elements, feature heterogeneity and salience, and health analytics. Using 7,614 imaging, clinical, and phenotypic features of 9,914 subjects we performed deep computed phenotyping using unsupervised clustering and derived two distinct sub-cohorts. Using parametric and nonparametric tests, we determined the top 20 most salient features contributing to the cluster separation. Our approach generated decision rules to predict the presence and progression of depression or other mental illnesses by jointly representing and modeling the significant clinical and demographic variables along with the derived salient neuroimaging features. We reported consistency and reliability measures of the derived computed phenotypes and the top salient imaging biomarkers that contributed to the unsupervised clustering. This clinical decision support system identified and utilized holistically the most critical biomarkers for predicting mental health, e.g., depression. External validation of this technique on different populations may lead to reducing healthcare expenses and improving the processes of diagnosis, forecasting, and tracking of normal and pathological aging.

Blood-brain barrier breakdown in the aging human hippocampus.

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.

Higher homocysteine associated with thinner cortical gray matter in 803 participants from the Alzheimer's Disease Neuroimaging Initiative.

A significant portion of our risk for dementia in old age is associated with lifestyle factors (diet, exercise, and cardiovascular health) that are modifiable, at least in principle. One such risk factor, high-homocysteine levels in the blood, is known to increase risk for Alzheimer's disease and vascular disorders. Here, we set out to understand how homocysteine levels relate to 3D surface-based maps of cortical gray matter distribution (thickness, volume, and surface area) computed from brain magnetic resonance imaging in 803 elderly subjects from the Alzheimer's Disease Neuroimaging Initiative data set. Individuals with higher plasma levels of homocysteine had lower gray matter thickness in bilateral frontal, parietal, occipital, and right temporal regions and lower gray matter volumes in left frontal, parietal, temporal, and occipital regions, after controlling for diagnosis, age, and sex and after correcting for multiple comparisons. No significant within-group associations were found in cognitively healthy people, patients with mild cognitive impairment, or patients with Alzheimer's disease. These regional differences in gray matter structure may be useful biomarkers to assess the effectiveness of interventions, such as vitamin B supplements, that aim to prevent homocysteine-related brain atrophy by normalizing homocysteine levels.

Shifting brain asymmetry: the link between meditation and structural lateralization.

Previous studies have revealed an increased fractional anisotropy and greater thickness in the anterior parts of the corpus callosum in meditation practitioners compared with control subjects. Altered callosal features may be associated with an altered inter-hemispheric integration and the degree of brain asymmetry may also be shifted in meditation practitioners. Therefore, we investigated differences in gray matter asymmetry as well as correlations between gray matter asymmetry and years of meditation practice in 50 long-term meditators and 50 controls. We detected a decreased rightward asymmetry in the precuneus in meditators compared with controls. In addition, we observed that a stronger leftward asymmetry near the posterior intraparietal sulcus was positively associated with the number of meditation practice years. In a further exploratory analysis, we observed that a stronger rightward asymmetry in the pregenual cingulate cortex was negatively associated with the number of practice years. The group difference within the precuneus, as well as the positive correlations with meditation years in the pregenual cingulate cortex, suggests an adaptation of the default mode network in meditators. The positive correlation between meditation practice years and asymmetry near the posterior intraparietal sulcus may suggest that meditation is accompanied by changes in attention processing.

Neurobehavioral comorbidities of pediatric epilepsies are linked to thalamic structural abnormalities.

PURPOSE: Neurobehavioral comorbidities are common in pediatric epilepsy with enduring adverse effects on functioning, but their neuroanatomic underpinning is unclear. Striatal and thalamic abnormalities have been associated with childhood-onset epilepsies, suggesting that epilepsy-related changes in the subcortical circuit might be associated with the comorbidities of children with epilepsy. We aimed to compare subcortical volumes and their relationship with age in children with complex partial seizures (CPS), childhood absence epilepsy (CAE), and healthy controls (HC). We examined the shared versus unique structural-functional relationships of these volumes with behavior problems, intelligence, language, peer interaction, and epilepsy variables in these two epilepsy syndromes. METHODS: We investigated volumetric differences of caudate, putamen, pallidum, and thalamus in children with CPS (N = 21), CAE (N = 20), and HC (N = 27). Study subjects underwent structural magnetic resonance imaging (MRI), intelligence, and language testing. Parent-completed Child Behavior Checklists provided behavior problem and peer interaction scores. We examined the association of age, intelligence quotient (IQ), language, behavioral problems, and epilepsy variables with subcortical volumes that were significantly different between the children with epilepsy and HC. KEY FINDINGS: Both children with CPS and CAE exhibited significantly smaller left thalamic volume compared to HC. In terms of developmental trajectory, greater thalamic volume was significantly correlated with increasing age in children with CPS and CAE but not in HC. With regard to the comorbidities, reduced left thalamic volumes were related to more social problems in children with CPS and CAE. Smaller left thalamic volumes in children with CPS were also associated with poor attention, lower IQ and language scores, and impaired peer interaction. SIGNIFICANCE: Our study is the first to directly compare and detect shared thalamic structural abnormalities in children with CPS and CAE. These findings highlight the vulnerability of the thalamus and provide important new insights on its possible role in the neurobehavioral comorbidities of childhood-onset epilepsy.

Meditation effects within the hippocampal complex revealed by voxel-based morphometry and cytoarchitectonic probabilistic mapping.

Scientific studies addressing anatomical variations in meditators' brains have emerged rapidly over the last few years, where significant links are most frequently reported with respect to gray matter (GM). To advance prior work, this study examined GM characteristics in a large sample of 100 subjects (50 meditators, 50 controls), where meditators have been practicing close to 20 years, on average. A standard, whole-brain voxel-based morphometry approach was applied and revealed significant meditation effects in the vicinity of the hippocampus, showing more GM in meditators than in controls as well as positive correlations with the number of years practiced. However, the hippocampal complex is regionally segregated by architecture, connectivity, and functional relevance. Thus, to establish differential effects within the hippocampal formation (cornu ammonis, fascia dentata, entorhinal cortex, subiculum) as well as the hippocampal-amygdaloid transition area, we utilized refined cytoarchitectonic probabilistic maps of (peri-) hippocampal subsections. Significant meditation effects were observed within the subiculum specifically. Since the subiculum is known to play a key role in stress regulation and meditation is an established form of stress reduction, these GM findings may reflect neuronal preservation in long-term meditators-perhaps due to an attenuated release of stress hormones and decreased neurotoxicity.

Global and regional alterations of hippocampal anatomy in long-term meditation practitioners.

Studies linking meditation and brain structure are still relatively sparse, but the hippocampus is consistently implicated as one of the structures altered in meditation practitioners. To explore hippocampal features in the framework of meditation, we analyzed high-resolution structural magnetic resonance imaging data from 30 long-term meditators and 30 controls, closely matched for sex, age, and handedness. Hippocampal formations were manually traced following established protocols. In addition to calculating left and right hippocampal volumes (global measures), regional variations in surface morphology were determined by measuring radial distances from the hippocampal core to spatially matched surface points (local measures). Left and right hippocampal volumes were larger in meditators than in controls, significantly so for the left hippocampus. The presence and direction of this global effect was confirmed locally by mapping the exact spatial locations of the group differences. Altogether, radial distances were larger in meditators compared to controls, with up to 15% difference. These local effects were observed in several hippocampal regions in the left and right hemisphere though achieved significance primarily in the left hippocampal head. Larger hippocampal dimensions in long-term meditators may constitute part of the underlying neurological substrate for cognitive skills, mental capacities, and/or personal traits associated with the practice of meditation. Alternatively, given that meditation positively affects autonomic regulation and immune activity, altered hippocampal dimensions may be one result of meditation-induced stress reduction. However, given the cross-sectional design, the lack of individual stress measures, and the limited resolution of brain data, the exact underlying neuronal mechanisms remain to be established.

Mapping connectivity damage in the case of Phineas Gage.

White matter (WM) mapping of the human brain using neuroimaging techniques has gained considerable interest in the neuroscience community. Using diffusion weighted (DWI) and magnetic resonance imaging (MRI), WM fiber pathways between brain regions may be systematically assessed to make inferences concerning their role in normal brain function, influence on behavior, as well as concerning the consequences of network-level brain damage. In this paper, we investigate the detailed connectomics in a noted example of severe traumatic brain injury (TBI) which has proved important to and controversial in the history of neuroscience. We model the WM damage in the notable case of Phineas P. Gage, in whom a "tamping iron" was accidentally shot through his skull and brain, resulting in profound behavioral changes. The specific effects of this injury on Mr. Gage's WM connectivity have not previously been considered in detail. Using computed tomography (CT) image data of the Gage skull in conjunction with modern anatomical MRI and diffusion imaging data obtained in contemporary right handed male subjects (aged 25-36), we computationally simulate the passage of the iron through the skull on the basis of reported and observed skull fiducial landmarks and assess the extent of cortical gray matter (GM) and WM damage. Specifically, we find that while considerable damage was, indeed, localized to the left frontal cortex, the impact on measures of network connectedness between directly affected and other brain areas was profound, widespread, and a probable contributor to both the reported acute as well as long-term behavioral changes. Yet, while significantly affecting several likely network hubs, damage to Mr. Gage's WM network may not have been more severe than expected from that of a similarly sized "average" brain lesion. These results provide new insight into the remarkable brain injury experienced by this noteworthy patient.

Bridging the hemispheres in meditation: thicker callosal regions and enhanced fractional anisotropy (FA) in long-term practitioners.

Recent findings suggest a close link between long-term meditation practices and the structure of the corpus callosum. Prior analyses, however, have focused on estimating mean fractional anisotropy (FA) within two large pre-defined callosal tracts only. Additional effects might exist in other, non-explored callosal regions and/or with respect to callosal attributes not captured by estimates of FA. To further explore callosal features in the framework of meditation, we analyzed 30 meditators and 30 controls, carefully matched for sex, age, and handedness. We applied a multimodal imaging approach using diffusion tensor imaging (DTI) in combination with structural magnetic resonance imaging (MRI). Callosal measures of tract-specific FA were complemented with other global (segment-specific) estimates as well as extremely local (point-wise) measures of callosal micro- and macro-structure. Callosal measures were larger in long-term meditators compared to controls, particularly in anterior callosal sections. However, differences achieved significance only when increasing the regional sensitivity of the measurement (i.e., using point-wise measures versus segment-specific measures) and were more prominent for microscopic than macroscopic characteristics (i.e., callosal FA versus callosal thickness). Thicker callosal regions and enhanced FA in meditators might indicate greater connectivity, possibly reflecting increased hemispheric integration during cerebral processes involving (pre)frontal regions. Such a brain organization might be linked to achieving characteristic mental states and skills as associated with meditation, though this hypothesis requires behavioral confirmation. Moreover, longitudinal studies are required to address whether the observed callosal effects are induced by meditation or constitute an innate prerequisite for the start or successful continuation of meditation.

The unique brain anatomy of meditation practitioners: alterations in cortical gyrification.

Several cortical regions are reported to vary in meditation practitioners. However, prior analyses have focused primarily on examining gray matter or cortical thickness. Thus, additional effects with respect to other cortical features might have remained undetected. Gyrification (the pattern and degree of cortical folding) is an important cerebral characteristic related to the geometry of the brain's surface. Thus, exploring cortical gyrification in long-term meditators may provide additional clues with respect to the underlying anatomical correlates of meditation. This study examined cortical gyrification in a large sample (n = 100) of meditators and controls, carefully matched for sex and age. Cortical gyrification was established by calculating mean curvature across thousands of vertices on individual cortical surface models. Pronounced group differences indicating larger gyrification in meditators were evident within the left precentral gyrus, right fusiform gyrus, right cuneus, as well as left and right anterior dorsal insula (the latter representing the global significance maximum). Positive correlations between gyrification and the number of meditation years were similarly pronounced in the right anterior dorsal insula. Although the exact functional implications of larger cortical gyrification remain to be established, these findings suggest the insula to be a key structure involved in aspects of meditation. For example, variations in insular complexity could affect the regulation of well-known distractions in the process of meditation, such as daydreaming, mind-wandering, and projections into past or future. Moreover, given that meditators are masters in introspection, awareness, and emotional control, increased insular gyrification may reflect an integration of autonomic, affective, and cognitive processes. Due to the cross-sectional nature of this study, further research is necessary to determine the relative contribution of nature and nurture to links between cortical gyrification and meditation.

Enhanced brain connectivity in long-term meditation practitioners.

Very little is currently known about the cerebral characteristics that underlie the complex processes of meditation as only a limited number of studies have addressed this topic. Research exploring structural connectivity in meditation practitioners is particularly rare. We thus acquired diffusion tensor imaging (DTI) data of high angular and spatial resolution and used atlas-based tract mapping methods to investigate white matter fiber characteristics in a well-matched sample of long-term meditators and controls (n=54). A broad field mapping approach estimated the fractional anisotropy (FA) for twenty different fiber tracts (i.e., nine tracts in each hemisphere and two inter-hemispheric tracts) that were subsequently used as dependent measures. Results showed pronounced structural connectivity in meditators compared to controls throughout the entire brain within major projection pathways, commissural pathways, and association pathways. The largest group differences were observed within the corticospinal tract, the temporal component of the superior longitudinal fasciculus, and the uncinate fasciculus. While cross-sectional studies represent a good starting point for elucidating possible links between meditation and white matter fiber characteristics, longitudinal studies will be necessary to determine the relative contribution of nature and nurture to enhanced structural connectivity in long-term meditators.

Diminished gray matter within the hypothalamus in autism disorder: a potential link to hormonal effects?

BACKGROUND: Subjects with autism suffer from impairments of social interaction, deviations in language usage, as well as restricted and stereotyped patterns of behavior. These characteristics are found irrespective of age, IQ, and gender of affected subjects. However, brain changes due to age, IQ, and gender might pose potential confounds in autism neuroimaging analyses. METHODS: To investigate gray matter differences in autism that are not related to these potential confounds, we performed a voxel-based morphometry analysis in 52 affected children and adolescents and 52 matched control subjects. RESULTS: We observed diminished gray matter in a region of the hypothalamus, which synthesizes the behaviorally relevant hormones oxytocin and arginine vasopressin. CONCLUSIONS: This finding provides support for further investigations of the theory of abnormal functioning of this hormonal system in autism and potentially for experimental therapeutic approaches with oxytocin and related neuropeptides.

Homocysteine effects on brain volumes mapped in 732 elderly individuals.

Elevated homocysteine levels are a known risk factor for Alzheimer's disease and vascular disorders. Here we applied tensor-based morphometry to brain magnetic resonance imaging scans of 732 elderly individuals from the Alzheimer's Disease Neuroimaging Initiative study, to determine associations between homocysteine and brain atrophy. Those with higher homocysteine levels showed greater frontal, parietal, and occipital white matter atrophy in the entire cohort, irrespective of diagnosis, age, or sex. This association was also found when considering mild cognitive impairment individuals separately. Vitamin B supplements, such as folate, may help prevent homocysteine-related atrophy in Alzheimer's disease by possibly reducing homocysteine levels. These atrophy profiles may, in the future, offer a potential biomarker to gauge the efficacy of interventions using dietary folate supplementation.

The underlying anatomical correlates of long-term meditation: larger hippocampal and frontal volumes of gray matter.

Although the systematic study of meditation is still in its infancy, research has provided evidence for meditation-induced improvements in psychological and physiological well-being. Moreover, meditation practice has been shown not only to benefit higher-order cognitive functions but also to alter brain activity. Nevertheless, little is known about possible links to brain structure. Using high-resolution MRI data of 44 subjects, we set out to examine the underlying anatomical correlates of long-term meditation with different regional specificity (i.e., global, regional, and local). For this purpose, we applied voxel-based morphometry in association with a recently validated automated parcellation approach. We detected significantly larger gray matter volumes in meditators in the right orbito-frontal cortex (as well as in the right thalamus and left inferior temporal gyrus when co-varying for age and/or lowering applied statistical thresholds). In addition, meditators showed significantly larger volumes of the right hippocampus. Both orbito-frontal and hippocampal regions have been implicated in emotional regulation and response control. Thus, larger volumes in these regions might account for meditators' singular abilities and habits to cultivate positive emotions, retain emotional stability, and engage in mindful behavior. We further suggest that these regional alterations in brain structures constitute part of the underlying neurological correlate of long-term meditation independent of a specific style and practice. Future longitudinal analyses are necessary to establish the presence and direction of a causal link between meditation practice and brain anatomy.

Grey and white matter loss along cerebral midline structures in myotonic dystrophy type 2.

Myotonic dystrophy type 2 (DM2) is an autosomal dominantly inherited multisystemic disorder and a common cause of muscular dystrophy in adults. Although neuromuscular symptoms predominate, there is clinical and imaging evidence of cerebral involvement. We used voxel-based morphometry (VBM) based on T1-weighted magnetic resonance images to investigate brain morphology in 13 DM2 patients in comparison to 13 sex- and age-matched controls. Further, we employed novel computational surface-based methods that specifically assess callosal thickness. We found grey and white matter loss along cerebral midline structures in our patient group. Grey matter reductions were present in brainstem and adjacent hypothalamic and thalamic regions, while white matter was mainly reduced in corpus callosum. The reduced callosal size was highly significant and independently confirmed by different methods. Our data provide first evidence for grey and white matter loss along brain midline structures in DM2 patients. The reduced size of the corpus callosum further extends the spectrum of white matter changes in DM2 and may represent the morphological substrate of neuropsychological abnormalities previously described in this disorder.

1H MRSI evidence of metabolic abnormalities in childhood-onset schizophrenia.

In adult schizophrenia, magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) have revealed volumetric and metabolic defects in multiple brain regions, among them the anterior cingulate, frontal cortex, striatum, thalamus, parietal cortex, and frontal and parietal white matter. This study used proton magnetic resonance spectroscopic imaging ((1)H MRSI) to identify potential metabolic abnormalities in these regions in childhood-onset schizophrenia. (1)H MRSI was acquired at 1.5 T and 272 ms echo time in 11 children and adolescents with schizophrenia (aged 7-18 years; seven boys, four girls; all but two medicated) and 20 age-matched healthy controls (10 boys, 10 girls). Absolute levels of N-acetyl compounds (NAA), creatine plus phosphocreatine (Cr), and choline compounds (Cho) were compared among groups in each region. In schizophrenic patients relative to controls, Cr was 14.3% higher in superior anterior cingulate (mean of left and right hemispheres). Cho was higher in superior anterior cingulate (30.3%), frontal cortex (13.3%), and caudate head (13.5%). In the thalamus, there was also a diagnosis-by-gender interaction, whereby NAA was lower in patients for male but not for female subjects. Elevated Cr suggests abnormal local cell-energy demand and elevated Cho is consistent with a prior proposal that patients with early age-of-onset schizophrenia exhibit phospholipid membrane disturbances. Low NAA may reflect diminished neuronal integrity.

Thought disorder and nucleus accumbens in childhood: a structural MRI study.

Thought disorder has been described as a hallmark feature in both adult and childhood-onset schizophrenia. The nucleus accumbens (NAc) has been repeatedly proposed as a critical station for modulating gating of information flow and processing of information within the thalamocortical circuitry. The aim of the present study was to investigate the relationship of thought disorder measures, which were administered to 12 children with schizophrenia and 15 healthy age-matched controls, and NAc volumes obtained from high-resolution volumetric magnetic resonance imaging analyses. The propensity for specific thought disorder features was significantly related to NAc volumes, despite no statistically significant differences in the NAc volumes of children with schizophrenia and normal children. Smaller left NAc volumes were significantly related to poor on-line revision of linguistic errors in word choice, syntax and reference. On the other hand, underuse of on-line repair of errors in planning and organizing thinking was significantly associated with decreased right NAc volumes. The results of this pilot study suggest that the NAc is implicated in specific thought patterns of childhood. They also suggest that subcortical function in the NAc might reflect hemispheric specialization patterns with left lateralization for revision of linguistic errors and right lateralization for repair strategies involved in the organization of thinking.