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PubMed2026

Novel epigenetic loci identified from an epigenome-wide association study underlying brain structural changes in bipolar disorder.

BACKGROUND: DNA methylation influences gene-environment interactions and brain development in bipolar disorder (BD). We aimed to identify BD-associated epigenetic loci and examine their associations with brain structural variation. METHODS: We conducted an epigenome-wide association study (BD group, n = 90; healthy controls group, n = 161) to identify BD-associated DNA methylation loci, and we additionally performed copy number alteration and functional enrichment analyses. The correlations between epigenetic loci and cortical thickness (CT) were assessed using Pearson's partial correlation analysis, and the co-methylation effect of the epigenetic loci identified in the neuroimaging-epigenetic analysis was investigated. FINDINGS: A total of 156 differentially methylated positions (DMPs) and 7 differentially methylated regions were identified, and the genes associated with them were observed to be enriched in biological processes related to muscle hypertrophy and neuronal activity. Significant correlations between the methylation levels of 13 DMPs associated with three genes (miR886, PLEC1, and ICAM5) and the CT of the right postcentral gyrus and inferior frontal gyrus were identified. Specifically, 10 DMPs associated with the CpG island in the upstream region of the miR886 gene showed negative correlations with the right postcentral gyrus CT, implicating miR886-associated CpG-island methylation in regional cortical thinning. CONCLUSION: Epigenetic changes might play an important role in brain structural changes in BD. These multimodal findings nominate miR886-related methylation as a candidate molecular correlate of cortical thinning and warrant replication and mechanistic follow-up in larger, state-diverse cohorts.

Humans↗
PubMed2004

Effect of monoamine oxidase gene knockout on dopamine metabolism in mouse brain structures.

Experiments were performed on knockout Tg8 mice lacking monoamine oxidase A gene that plays a major role in dopamine catabolism. The study by the method of high-performance liquid chromatography revealed considerable regional differences in the contents of dopamine and its metabolite dihydroxyphenylacetic acid in brain structures of these animals. Tg8 mice differed from the parent C3H/HeJ strain by low level of dihydroxyphenylacetic acid in the striatum, midbrain, hypothalamus, and hippocampus and high concentration of dopamine in the striatum. No differences were revealed in the contents of dopamine and dihydroxyphenylacetic acid in the frontal cortex and amygdala. The 2.4-4.8-fold decrease in the content of dihydroxyphenylacetic acid in various brain structures was not accompanied by changes in dopamine concentration. These data reflect the effective compensation for deficiency of dopamine metabolism. Our results suggest that monoamine oxidases A and B and catechol-O-methyltransferase play different roles in dopamine metabolism in various brain structures.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

An automated registration algorithm for measuring MRI subcortical brain structures.

An automated registration algorithm was used to elastically match an anatomical magnetic resonance (MR) atlas onto individual brain MR images. Our goal was to evaluate the accuracy of this procedure for measuring the volume of MRI brain structures. We applied two successive algorithms to a series of 28 MR brain images, from 14 schizophrenia patients and 14 normal controls. First, we used an automated segmentation program to differentiate between white matter, cortical and subcortical gray matter, and cerebrospinal fluid. Next, we elastically deformed the atlas segmentation to fit the subject's brain, by matching the white matter and subcortical gray matter surfaces. To assess the accuracy of these measurements, we compared, on all 28 images, 11 brain structures, measured with elastic matching, with the same structures traced manually on MRI scans. The similarity between the measurements (the relative difference between the manual and the automated volume) was 97% for whole white matter, 92% for whole gray matter, and on average 89% for subcortical structures. The relative spatial overlap between the manual and the automated volumes was 97% for whole white matter, 92% for whole gray matter, and on average 75% for subcortical structures. For all pairs of structures rendered with the automated and the manual method, Pearson correlations were between r = 0.78 and r = 0.98 (P < 0.01, N = 28), except for globus pallidus, where r = 0.55 (left) and r = 0. 44 (right) (P < 0.01, N = 28). In the schizophrenia group, compared to the controls, we found a 16.7% increase in MRI volume for the basal ganglia (i.e., caudate nucleus, putamen, and globus pallidus), but no difference in total gray/white matter volume or in thalamic MR volume. This finding reproduces previously reported results, obtained in the same patient population with manually drawn structures, and suggests the utility/efficacy of our automated registration algorithm over more labor-intensive manual tracings.

Adolescent↗
PubMed2005

Computational biology for visualization of brain structure.

The complexity and variability of human brain (as well as other species) across subjects is so great that reliance on maps and atlases is essential to effectively manipulate, analyze and interpret brain data. Central to these tasks is the construction of averages, templates and models to describe how the brain and its component parts are organized. Design of appropriate reference systems and visualization strategies for human brain data presents considerable challenges, since these systems must capture how brain structure and function vary in large populations, across age and gender, in different disease states, across imaging modalities and even across species. This paper will describe the application of brain maps to a variety of questions and problems in health and disease. It includes a brief survey of different types of maps, including those that capture dynamic patterns of brain change over time.

Algorithms↗
PubMed2001

Cerebral asymmetry and the effects of sex and handedness on brain structure: a voxel-based morphometric analysis of 465 normal adult human brains.

We used voxel-based morphometry (VBM) to examine human brain asymmetry and the effects of sex and handedness on brain structure in 465 normal adults. We observed significant asymmetry of cerebral grey and white matter in the occipital, frontal, and temporal lobes (petalia), including Heschl's gyrus, planum temporale (PT) and the hippocampal formation. Males demonstrated increased leftward asymmetry within Heschl's gyrus and PT compared to females. There was no significant interaction between asymmetry and handedness and no main effect of handedness. There was a significant main effect of sex on brain morphology, even after accounting for the larger global volumes of grey and white matter in males. Females had increased grey matter volume adjacent to the depths of both central sulci and the left superior temporal sulcus, in right Heschl's gyrus and PT, in right inferior frontal and frontomarginal gyri and in the cingulate gyrus. Females had significantly increased grey matter concentration extensively and relatively symmetrically in the cortical mantle, parahippocampal gyri, and in the banks of the cingulate and calcarine sulci. Males had increased grey matter volume bilaterally in the mesial temporal lobes, entorhinal and perirhinal cortex, and in the anterior lobes of the cerebellum, but no regions of increased grey matter concentration.

Adolescent↗
PubMedDate not supplied

[Effect of centrophenoxine, piracetam and aniracetam on the monoamine oxidase activity in different brain structures of rats].

In vitro studies of effects of some nootropic drugs (centrophenoxine, piracetam and aniracetam) on monoamine oxidase (MAO) activity in the rat striatum and hypothalamus, using tyramine, serotonin and beta-phenylethylamine as substrates, were carried out. At all concentrations used (5.10(-5)-1.10(-3) M) centrophenoxine inhibited total MAO, MAO A and MAO B in both brain structures. Piracetam activated striatal and hypothalamic total MAO, hypothalamic MAO A and MAO B but exerted a pronounced inhibitory effect on MAO A and MAO B activity in the striatum. Aniracetam inhibited total MAO and MAO A in both brain structures but activated striatal and hypothalamic MAO B. The different effects of centrophenoxine, piracetam and aniracetam on MAO activity in the brain structures support the view for the independent mode of action of nootropic drugs in spite of their similar molecular and metabolic activity.

Animals↗
PubMed1997

Microhabitat use, trophic patterns, and the evolution of brain structure in African cichlids.

The species assemblages of cichlids in the three largest African Great Lakes are among the richest concentrations of vertebrate species on earth. The faunas are broadly similar in terms of trophic diversity, species richness, rates of endemism, and taxonomic composition, yet they are historically independent of each other. Hence, they offer a true and unique evolutionary experiment to test hypotheses concerning the mutual dependencies of ecology and brain morphology. We examined the brains of 189 species of cichlids from the three large lakes: Victoria, Tanganyika, and Malawi. A first paper demonstrated that patterns of evolutionary change in cichlid brain morphology are similar across taxonomic boundaries as well as across the three lakes [van Staaden et al., 1995 ZACS 98: 165-178]. Here we report a close relationship between the relative sizes of various brain structures and variables related to the utilization of habitat and prey. Causality is difficult to assign in this context, nonetheless, prey size and agility, turbidity levels, depth, and substrate complexity are all highly predictive of variation in brain structure. Areas associated with primary sensory functions such as vision and taste relate significantly to differences in feeding habits. Turbidity and depth are closely associated with differences in eye size, and large eyes are associated with species that pick plankton from the water column. Piscivorous taxa and others that utilize motile prey are characterized by a well developed optic tectum and a large cerebellum compared to species that prey on molluscs or plants. Structures relating to taste are well developed in species feeding on benthos over muddy or sandy substrates. The data militated against the existence of compensatory changes in brain structure. Thus enhanced development of a particular function is generally not accompanied by a parallel reduction of structures related to other modalities. Although genetic and environmental influences during ontogeny of the brain cannot be isolated, this study provides a rich source of hypotheses concerning the way the nervous system functions under various environmental conditions and how it has responded to natural selection.

Africa↗
PubMedDate not supplied

[The effect of starvation of lipid peroxidation in synaptosomal and mitochondrial factions of various brain structures].

Content of lipid hydroperoxides (LHP) and malonic dialdehyde (MDA) was measured in homogenates of rat brain cortex (limbic, sensomotor and orbital cortex) and subcortex brain structures (hypothalamus, medulla oblongata, and midbrain) and in their synaptosomal and mitochondrial fractions within various periods of starvation 1, 2, 3, 5 and 7 days. Lipid peroxidation was shown to intensify distinctly in the brain regions studied especially in the sensomotor cortex only after relatively long-term starvation during 5-7 days. The rate of lipid peroxidation was considerably higher in mitochondrial fractions of these brain structures studied than in the synaptosomes; high contents of LHP and MDA was found in mitochondria. Activation of lipid peroxidation appears to be distinctly responsible for impairment of the structure and functional components of nervous cells occurring during long-term starvation.

Animals↗
PubMed1991

[Two-dimensional electrophoretic analysis of the protein spectrum of human brain structures in schizophrenia and senile dementia of the Alzheimer type].

Analysis was made of the composition of four structures of human brain in health (n-12), schizophrenia (n-10), and Alzheimer's senile dementia (n-8). Protein maps obtained by means of two-dimensional electrophoresis were used to analyze tissue samples of the structures under study. In the investigation, the neocortex was represented by the frontal cortex (field 10), the old cortex by the hippocamp, the midbrain by black substance, and medulla oblongata by the inferior olive. Comparative study of the protein maps revealed quantitative differences in certain brain structures in health as well as differences between these structures in health and mental pathology.

Aged↗
PubMed2006

Children with new-onset epilepsy: neuropsychological status and brain structure.

Abnormalities in cognition, academic performance and brain volumetrics have been reported in children with chronic epilepsy. The nature and degree to which these problems may be present at epilepsy onset or may instead become more evident over time remains to be determined. This study characterizes neuropsychological status, brain structure and their interrelationship in children with recent-onset epilepsy compared with healthy controls. Children (age: 8-18 years) with recent-onset idiopathic epilepsy (n = 53) and healthy controls (n = 50) underwent comprehensive neuropsychological assessment and quantitative volumetric measurement of segmented (grey and white matter) volumes of total cerebrum and lobar regions. Compared with controls, children with recent-onset epilepsy exhibit a pattern of mild diffuse cognitive impairment, regardless of epilepsy syndrome, as well as academic underachievement that in a subset of children antedates the first recognized seizure. There are no overall differences in MR morphometric analyses of total cerebral or lobar tissue volumes. Controls show a strong association between cognitive development and increasing cerebral tissue volume (especially white matter volume), an association that is absent in children with epilepsy. Children with a history of academic achievement problems exhibit the most abnormal cognitive function and have significant volumetric reductions in left occipital and parietal lobe grey matter. Patients with idiopathic epilepsy exhibit cognitive dysfunction and academic underachievement at the onset of the disorder, irrespective of epilepsy syndrome, and indications of antecedent neurocognitive impairment are present in a subset of children. Volumetric abnormalities are not yet apparent in the epilepsy group as a whole, but there are indications of an altered structure-function relationship in epilepsy, and the subset of children with prior history of academic problems have abnormal volume of posterior left hemisphere grey matter. These early abnormalities need to be integrated into lifespan models of the neuropsychology of epilepsy.

Adolescent↗
PubMed2004

Sex-specific, postpuberty changes in mouse brain structures revealed by three-dimensional magnetic resonance microscopy.

Sexual dimorphism of brain structures has been reported in some species. We report that sex-dependent developmental structure changes exist in the C57Bl/6(J) mouse, a common model for the genetic analysis of brain function. High resolution, three-dimensional (3D) magnetic resonance microscopy (MRM) images were obtained in intact brains of male and female adult and peripubertal mice. The lateral and third ventricles, hippocampus, amygdala, striatum, and total brain were reconstructed in 3D. As observed in humans, there was overall cerebral growth from peripuberty to adulthood in both sexes. After correcting for the increased brain size, the hippocampus and amygdala were disproportionately larger in adult compared to peripubertal mice. Several sexual dimorphisms were also observed. The lateral ventricles were larger, while the amygdala (the left side in particular) was smaller in females compared to males. Lateral and third ventricles were reduced over time in males only, exhibiting a sex-specific developmental profile. The striatal size was uniform among the groups studied. The surface area of the segmented structures was assayed. Possible shape distortions were detected for the lateral ventricles, hippocampus, and overall brain structure based on a lack of covariance between the surface area and volumetric measurements. Although many sexually dimorphic changes are reported perinatally, our results suggest that there are additional sex-specific transformations that occur around puberty and persist in adulthood.

Animals↗
PubMed1988

A biochemical and immunohistological study of calmodulin in rat brain structures.

Calmodulin content and immunoreactivity in rat brain structures, believed to be essential site involved in plasticity events, were determined by using biochemical and immunohistochemical methods, respectively. The levels of cytosolic and membrane-bound calmodulin paralleled the overall distribution pattern of calmodulin immunoreactivity. Very intense immunoreactivity was observed in neuronal structures of hippocampus, striatum and mesencephalon. White matter structures and, especially, myelinated nerve fibres did not reveal calmodulin immunoreactivity. Thus, the present findings are consistent with data reported in the literature that calmodulin, unlike to other calcium-binding proteins, is primarily associated with neuronal elements. The present findings support the usefulness of calmodulin studies in elucidating of cellular mechanisms underlying neuronal plasticity.

Animals↗
PubMed1989

Biochemical evidence for the GABA regulation of vasopressin levels in microdissected brain structures after servo-controlled hypotension.

Discrete brain structures were analysed for gamma-aminobutyric acid (GABA) and vasopressin content in normo- and hypotensive rats treated with the glutamic acid decarboxylase inhibitor, 3-mercaptopropionic acid (MPA) and the GABAA agonist muscimol. In the normotensive group treated with MPA only, the concentration of vasopressin increased in the supraoptic nucleus, indicating an inhibitory role for GABA. In the hypotensive group a rise in the vasopressin level in the nucleus of the solitary tract was detected and the GABA level decreased in the supraoptic nucleus. Muscimol decreased the concentration of vasopressin in the nucleus of the solitary tract. The changes in the concentration of vasopressin may be a result of increased or decreased activation of the GABAergic system. The results show that the GABA- and vasopressinergic systems somehow interact although the more precise way of action remains to be clarified.

3-Mercaptopropionic Acid↗
PubMed2001

Separate and interactive effects of cocaine and alcohol dependence on brain structures and metabolites: quantitative MRI and proton MR spectroscopic imaging.

The effects of chronic cocaine and alcohol abuse on human brain structure and metabolites are not fully known. We studied controls (n = 13) and abstinent subjects dependent on cocaine (8), alcohol (12), and cocaine and alcohol (17) using quantitative MRI and proton MR spectroscopic imaging. Talairach-based techniques yielded tissue and CSF volumes and gray- and white-matter concentrations of N-acetylaspartate (NAA), creatine and choline metabolites in multiple brain regions. Alcohol dependents had lower gray-matter NAA concentrations and more sulcal CSF than non-alcohol dependents throughout the brain. They also had less subcortical gray matter and (regionally) less white matter. Cocaine dependents compared with non-cocaine dependents had higher posterior parietal white-matter creatine concentration. They also had less gray and white matter in the prefrontal lobes and in a region encompassing the temporal lobes and cerebellum. Structural white-matter deficits in cocaine dependents were greater with longer duration of cocaine use. Subjects with concurrent cocaine and alcohol dependence had less prefrontal white matter, especially in the anterior cingulate, than subjects dependent on only one substance. Chronically abused cocaine and alcohol each leave multiple metabolic and structural brain defects after long-term abstinence. Concurrent dependence on both substances may aggravate white-matter structural defects, primarily in frontal brain.

Journal Article↗
PubMed2002

The neurodevelopmental impact of childhood-onset temporal lobe epilepsy on brain structure and function.

PURPOSE: To characterize the neurodevelopmental correlates of childhood-onset temporal lobe epilepsy on brain structure and cognition compared with late-onset chronic temporal lobe epilepsy and healthy controls. METHODS: Healthy controls (n = 62) and patients with early (n = 37) versus late (n = 16) age at onset of temporal lobe epilepsy were compared with high-resolution quantitative magnetic resonance imaging (MRI) volumetrics and comprehensive neuropsychological assessment. RESULTS: Patients with childhood-onset temporal lobe epilepsy (mean onset age, 7.8 years) exhibited widespread compromise in neuropsychological performance and substantial reduction in brain tissue volumes extending to extratemporal regions compared with healthy controls and late-onset temporal lobe epilepsy patients (mean onset age, 23.3 years). Most evident was reduced total white-matter volume among the childhood-onset patients. Reduction in brain tissue volume, especially total white-matter volume, was associated with significantly poorer cognitive status, attesting to the clinical significance of the volumetric abnormalities. CONCLUSIONS: Childhood-onset temporal lobe epilepsy appears to be associated with an adverse neurodevelopmental impact on brain structure and cognition that appears generalized in nature and especially evident in white-matter tissue volume.

Adolescent↗
PubMedDate not supplied

[Effect of early visual deprivation on GABA transaminase activity in the brain structures of dogs].

Activity of GABA-transaminase was distinctly decreased as compared with controls in all the brain structures studied in animals growing under conditions of early visual deprivation. At the same time, alterations were developed in synthesis of glutamic and aspartic acids and in their ratio. Biosynthesis of glutamic acid was decreased 2-fold in parietal cortex region and in cerebellum of 45 day-old animals, less distinct decrease in the amino acid synthesis was observed in the locomotion brain region of the animals as compared with controls. At an age of 90 days, to the contrary, most distinct decrease (3-fold) in glutamic acid synthesis occurred in the locomotion region and a less distinct decrease - in cerebellum. Synthesis of aspartic acid was less distinctly altered in the deprived animals; it was decreased in cerebellum of both age groups of animals, in parietal cortex region - only in the group of 90 day-old animals and unaltered - in locomotion region of both animal groups. The values of the glutamic/aspartic acid ratio were also decreased. The pattern was quite similar in all the brain structures studied of 45 day-old animals; in the 90 day-old animals the corresponding ratios of the amino acids were increased in cerebellum, only slightly increased - in locomotion region of brain cortex and they were decreased in parietal cortex region.

4-Aminobutyrate Transaminase↗
PubMed2001

Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization.

Mental function has as its cerebral basis a specific dynamic structure. In particular, cortical and limbic areas involved in "higher brain functions" such as learning, memory, perception, self-awareness and consciousness continuously need to be self-adjusted even after development is completed. By this lifelong self-optimization process, the cognitive, behavioural and emotional reactivity of an individual is stepwise remodelled to meet the environmental demands. While the presence of rigid synaptic connections ensures the stability of the principal characteristics of function, the variable configuration of the flexible synaptic connections determines the unique, non-repeatable character of an experienced mental act. With the increasing need during evolution to organize brain structures of increasing complexity, this process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. These mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodelling according to experience, are accompanied, however, by increasing inherent possibilities of failure and may, thus, not only allow for the evolutionary acquisition of "higher brain function" but at the same time provide the basis for a variety of neuropsychiatric disorders. It is the objective of the present paper to outline the hypothesis that it might be the disturbance of structural brain self-organization which, based on both genetic and epigenetic information, constantly "creates" and "re-creates" the brain throughout life, that is the defect that underlies Alzheimer's disease (AD). This hypothesis is, in particular, based on the following lines of evidence. (1) AD is a synaptic disorder. (2) AD is associated with aberrant sprouting at both the presynaptic (axonal) and postsynaptic (dendritic) site. (3) The spatial and temporal distribution of AD pathology follows the pattern of structural neuroplasticity in adulthood, which is a developmental pattern. (4) AD pathology preferentially involves molecules critical for the regulation of modifications of synaptic connections, i.e. "morphoregulatory" molecules that are developmentally controlled, such as growth-inducing and growth-associated molecules, synaptic molecules, adhesion molecules, molecules involved in membrane turnover, cytoskeletal proteins, etc. (5) Life events that place an additional burden on the plastic capacity of the brain or that require a particularly high plastic capacity of the brain might trigger the onset of the disease or might stimulate a more rapid progression of the disease. In other words, they might increase the risk for AD in the sense that they determine when, not whether, one gets AD. (6) AD is associated with a reactivation of developmental programmes that are incompatible with a differentiated cellular background and, therefore, lead to neuronal death. From this hypothesis, it can be predicted that a therapeutic intervention into these pathogenetic mechanisms is a particular challenge as it potentially interferes with those mechanisms that at the same time provide the basis for "higher brain function".

Alzheimer Disease↗
PubMedDate not supplied

[Neuropharmacological study of the joint action of verapamil and olanzapine on the content of neurotransmitters in Wistar rat brain structures].

The effects of jointly administered olanzapine and verapamil on the level of neurotransmitters and their metabolites in Wistar rat brain structures have been studied. Verapamil (i) produces a statistically significant decrease in dopamine and serotonin turnover increased by olanzapine injections and (ii) increases the norepinephrine content in all the brain structures studied.

Animals↗