Loss of glial glutamate transporters and induction of neuronal expression of GLT-1B in the hypoxic neonatal pig brain

The homeostasis of glutamate is critical to normal brain function; deficiencies in the regulation of extracellular glutamate are thought to be a major determinant of damage in hypoxic brains. Extracellular levels of glutamate are regulated mainly by plasmalemmal glutamate transporters. We have evaluated the distribution of the glutamate transporter GLAST and two splice variants of GLT-1 in the hypoxic neonatal pig brain using this as model of neonatal humans. In response to severe hypoxic insults, we observe a rapid loss of two glial glutamate transporters from specific brain regions, such as the CA1 region of the hippocampus, but not the dentate gyrus. The spatial distribution of loss accords with patterns of damage in these brains. Conversely, we demonstrate that hypoxia evokes the expression of a splice variant of GLT-1 in neurons. We suggest that this expression may be induced in response to elevated extracellular glutamate around these neurons, and that this splice variant may represent a useful marker for direct quantification of the extent of likely neuronal damage in hypoxic brains. © 2004 Elsevier B.V. All rights reserved.

Alzheimer's disease: size class frequency distribution of senile plaques: do they indicate when a brain tissue was affected?

The size class frequency distribution of a sample of senile plaques (SP) was determined in a total of 20 brain regions from 5 elderly cases of Alzheimer's disease (AD). The purpose of the study was to determine whether a comparison of the frequency distributions could be used to determine the chronology of SP development in the AD brain. SP from 10 microns to a maximum diameter of 160 microns were present in the tissue and the size class frequency distributions were positively skewed. The frequency distributions varied between brain regions in: (1) the size class containing the mode, (2) the degree of positive skew, and (3) the ratio of large to small SP. In most patients the ratio of large to small SP was higher in the hippocampus or adjacent gyrus compared with temporal, parietal and frontal neocortex. If the diameter of a SP reflects its age in the tissue than the data suggest that SP formed earlier either in the hippocampus or adjacent gyrus compared with the other neocortical tissues. However, this conclusion rests on a number of assumptions including: (1) that SP diameter is directly related to age, (2) that SP development occurs at similar rates in different brain regions and (3) that, once formed, SP are not removed from the tissue by astrocytes.

Experiments and observations on the behaviour and brain of the aging female mouse with special reference to dementia of the Alzheimer type

The objective of this research was to investigate the effects of normal aging and the additional effects of chronic exposure to two experimental diets, one enriched in aluminium, the other enriched in lecithin, on aspects of the behaviour and brain histology of the female mouse. The aluminium diet was administered in an attempt to develop a rodent model of Dementia of the Alzheimer Type (DAT). With normal aging, almost all assessed aspects of behaviour were found to be impaired. As regards cognition, selective impairments of single-trial passive avoidance and Morris place learning were observed. While all aspects of open-field behaviour were impaired, the degree of impairment was directly related to the degree of motoric complexity. Deficits were also observed on non-visual sensorimotor coordination tasks and in olfactory discrimination. Histologically, neuron loss, gliosis, vacuolation and congophilic angiopathy were observed in several of the brain regions/fibre tracts believed to contribute to the control of some of the assessed behaviours. The aluminium treatment had very selective effects on both behaviour and brain histology, inducing several features observed in DAT. Behaviourally, the treatment induced impaired spatial reference memory; reduced ambulation; disturbed olfactory function and induced the premature development of the senile pattern of swimming. Histologically, significant neuron loss and gliosis were observed in the hippocampus, entorhinal cortex, amygdala, medial septum, pyriform and pr-frontal cortex. In addition, the brain distribution of congophilic angiopathy was significantly increased by the treatment. The lecithin treatment had effects on both non-cognitive and cognitive aspects of behaviour. The effects of aging on open-field ambulation and rearing were partially ameliorated by the treatment. A similar effect was observed for single-trial passive avoidance performance. Age-dependent improvements in acquisition/retention were observed in 17-23 month mice and Morris place task performance was improved in 11 and 17 month mice. Histologically, a partial sparing of neurons in the cerebellum, hippocampus, entorhinal cortex and subiculum was observed.

β-amyloid (Aβ) deposition in cognitively normal brain, dementia with Lewy bodies, and Alzheimer's disease:a study using principal components analysis

The densities of diffuse, primitive, and classic ß-amyloid (Aß) deposits were studied in the temporal lobe in cognitively normal brain, dementia with Lewy bodies (DLB), familial Alzheimer’s disease (FAD), and sporadic AD (SAD). Principal components analysis (PCA) was used to determine whether there were distinct differences between groups or whether Aß pathology was more continuously distributed from group to group. Three principal components (PC) were extracted from the data accounting for 56% of the total variance. Plots of cases in relation to the PC did not result in distinct groups but suggested overlap in Aß deposition between the groups. In addition, there were linear correlations between the densities of Aß deposits and the distribution of the cases along the PC in specific brain regions suggesting continuous variation from group to group. PC1 was associated with the degree of maturation of Aß deposits, PC2 with differences between FAD and SAD, and PC3 with the degree of spread of Aß pathology into the hippocampus. Apolipoprotein E (APOE) genotype was not associated with variation in Aß deposition between cases. PCA may be a useful method of studying the pathological interface between closely related neurodegenerative disorders.

No gender differences in brain activation during the N-back task:An fMRI study in healthy individuals

Gender differences have been well established in verbal and spatial abilities but few studies have examined if these differences also extend into the domain of working memory in terms of behavioural differences and brain activation. The conclusions that can be drawn from these studies are not clear cut but suggest that even though gender differences might not be apparent from behavioural measures, the underlying neural substrate associated with working memory might be different in men and women. Previous research suggests activation in a network of frontal and parietal regions during working memory tasks. This study aimed to investigate gender differences in patterns of brain activation during a verbal version of the N-back working memory task, which incorporates the effects of increased demands on working memory. A total of 50 healthy subjects, aged 18 to 58 years, that were equally split by gender were recruited matched for age, levels of education and ethnicity. All subjects underwent functional magnetic resonance imaging. We found that men and women performed equally well in terms of accuracy and response times, while using similar brain regions to the same degree. Our observations indicate that verbal working memory is not affected by gender at the behavioural or neural level, and support the findings of a recent meta-analysis by Hyde ([2005]: Sex Roles 53:717-725) that gender differences are generally smaller than intra-gender differences in many cognitive domains. © 2009 Wiley-Liss, Inc.

Where do bright ideas occur in our brain? Meta-analytic evidence from neuroimaging studies of domain-specific creativity

Many studies have assessed the neural underpinnings of creativity, failing to find a clear anatomical localization. We aimed to provide evidence for a multi-componential neural system for creativity. We applied a general activation likelihood estimation (ALE) meta-analysis to 45 fMRI studies. Three individual ALE analyses were performed to assess creativity in different cognitive domains (Musical, Verbal, and Visuo-spatial). The general ALE revealed that creativity relies on clusters of activations in the bilateral occipital, parietal, frontal, and temporal lobes. The individual ALE revealed different maximal activation in different domains. Musical creativity yields activations in the bilateral medial frontal gyrus, in the left cingulate gyrus, middle frontal gyrus, and inferior parietal lobule and in the right postcentral and fusiform gyri. Verbal creativity yields activations mainly located in the left hemisphere, in the prefrontal cortex, middle and superior temporal gyri, inferior parietal lobule, postcentral and supramarginal gyri, middle occipital gyrus, and insula. The right inferior frontal gyrus and the lingual gyrus were also activated. Visuo-spatial creativity activates the right middle and inferior frontal gyri, the bilateral thalamus and the left precentral gyrus. This evidence suggests that creativity relies on multi-componential neural networks and that different creativity domains depend on different brain regions.

Introduction of novel video-based tasks to clinical fMRI: Comparing traditional fMRI tasks with novel video-based tasks for mapping brain language areas

Recently, blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has become a routine clinical procedure for localization of language and motor brain regions and has been replacing more invasive preoperative procedures. However, the fMRI results from these tasks are not always reproducible even from the same patient. Evaluating the reproducibility of language and speech mapping is especially complicated due to the complex brain circuitry that may become activated during the functional task. Non-language areas such as sensory, attention, decision-making, and motor brain regions may also be activated in addition to the specific language regions during a traditional sentence-completion task. In this study, I test a new approach, which utilizes 4-minute video-based tasks, to map language and speech brain regions for patients undergoing brain surgery. Results from 35 subjects have shown that the video-based task activates Wernicke’s area, as well as Broca’s area in most subjects. The computed laterality indices, which indicate the dominant hemisphere from that functional task, have indicated left dominance from the video-based tasks. This study has shown that the video-based task may be an alternative method for localization of language and speech brain regions for patients who are unable to complete the sentence-completion task.

Information-Based Approaches of Noninvasive Transcranial Brain Stimulation

Progress in cognitive neuroscience relies on methodological developments to increase the specificity of knowledge obtained regarding brain function. For example, in functional neuroimaging the current trend is to study the type of information carried by brain regions rather than simply compare activation levels induced by task manipulations. In this context noninvasive transcranial brain stimulation (NTBS) in the study of cognitive functions may appear coarse and old fashioned in its conventional uses. However, in their multitude of parameters, and by coupling them with behavioral manipulations, NTBS protocols can reach the specificity of imaging techniques. Here we review the different paradigms that have aimed to accomplish this in both basic science and clinical settings and follow the general philosophy of information-based approache

Metabolic signatures of Huntington's disease (HD): 1H NMR analysis of the polar metabolome in post mortem human brain

Huntington’s disease (HD) is an autosomal neurodegenerative disorder affecting approximately 5-10 persons per 100,000 worldwide. The pathophysiology of HD is not fully understood but the age of onset is known to be highly dependent on the number of CAG triplet repeats in the huntingtin gene. Using 1H NMR spectroscopy this study biochemically profiled 39 brain metabolites in post-mortem striatum (n=14) and frontal lobe (n=14) from HD sufferers and controls (n=28). Striatum metabolites were more perturbed with 15 significantly affected in HD cases, compared with only 4 in frontal lobe (P<0.05; q<0.3). The metabolite which changed most overall was urea which decreased 3.25-fold in striatum (P<0.01). Four metabolites were consistently affected in both brain regions. These included the neurotransmitter precursors tyrosine and L-phenylalanine which were significantly depleted by 1.55-1.58-fold and 1.48-1.54-fold in striatum and frontal lobe, respectively (P=0.02-0.03). They also included L-leucine which was reduced 1.54-1.69-fold (P=0.04-0.09) and myo-inositol which was increased 1.26-1.37-fold (P<0.01). Logistic regression analyses performed with MetaboAnalyst demonstrated that data obtained from striatum produced models which were profoundly more sensitive and specific than those produced from frontal lobe. The brain metabolite changes uncovered in this first 1H NMR investigation of human HD offer new insights into the disease pathophysiology. Further investigations of striatal metabolite disturbances are clearly warranted.

Classifying Child Maltreatment by Brain Imaging Data

Thesis (Master's)--University of Washington, 2016-08

MEG-measured visually induced gamma-band oscillations in chronic schizophrenia: Evidence for impaired generation of rhythmic activity in ventral stream regions

Background: Gamma-band oscillations are prominently impaired in schizophrenia, but the nature of the deficit and relationship to perceptual processes is unclear. Methods: 16 patients with chronic schizophrenia (ScZ) and 16 age-matched healthy controls completed a visual paradigm while magnetoencephalographic (MEG) data was recorded. Participants had to detect randomly occurring stimulus acceleration while viewing a concentric moving grating. MEG data were analyzed for spectral power (1-100 Hz) at sensorand source-level to examine the brain regions involved in aberrant rhythmic activity, and for contribution of differences in baseline activity towards the generation of low- and highfrequency power. Results: Our data show reduced gamma-band power at sensor level in schizophrenia patients during stimulus processing while alpha-band and baseline spectrum were intact. Differences in oscillatory activity correlated with reduced behavioral detection rates in the schizophrenia group and higher scores on the “Cognitive Factor” of the Positive and Negative Syndrome Scale. Source reconstruction revealed that extra-striate (fusiform/lingual gyrus), but not striate (cuneus), visual cortices contributed towards the reduced activity observed at sensorlevel in ScZ patients. Importantly, differences in stimulus-related activity were not due to differences in baseline activity. Conclusions: Our findings highlight that MEG-measured high-frequency oscillations during visual processing can be robustly identified in ScZ. Our data further suggest impairments that involve dysfunctions in ventral stream processing and a failure to increase gamma-band activity in a task-context. Implications of these findings are discussed in the context of current theories of cortical-subcortical circuit dysfunctions and perceptual processing in ScZ.

Effects of unilateral visual deprivation on the developing avian brain

The effect of varying states of visual deprivation on the development of the optic lobes and cerebral hemispheres has been studied in the chick where the visual pathways are totally crossed over. Unilateral eye extirpation of the new hatched chick resulted in arrested development of the contralateral but not ipsilateral lobe, as measured by weight, protein content and acetylcholinesterase activity. Similar effects but of smaller magnitude were observed in the cerebral hemispheres. Histologic and enzymic evidence revealed the absence of significant degeneration in the optic lobe contralateral to an eye removed 17 days previously. These results were observed in the optic lobes of operated animals maintained either in light of in darkness between 3 and 17 days after hatch. However, in the inpaired cerebral hemispheres, differences could only be detected in birds kept the light. The effects of unilateral eyelid suturing on the development of chick brain regions were also examined. In this group, all asymmetrical differences observed within paired brain regions were totally light dependent and confined to the cerebral hemispheres. The hemisphere contralateral to the sutured eye weighed less and had less acetylcholinesterase activity than its paired hemisphere. The cerebral hemispheres of monocularly treated birds manifested effects of similar magnitude whether the treatment was enucleation or suturing. This suggests that the complete development of the associative centers in avian cerebral hemispheres is dependent on both intact innervation and on the information content of the visual input. © 1969.

Agonistic interactions elicit rapid changes in brain nonapeptide levels in zebrafish

The teleost fish nonapeptides, arginine vasotocin (AVT) and isotocin (IT), have been implicated in the regulation of social behavior. These peptides are expected to be involved in acute and transient changes in social context, in order to be efficient in modulating the expression of social behavior according to changes in the social environment. Here we tested the hypothesis that short-term social interactions are related to changes in the level of both nonapeptides across different brain regions. For this purpose we exposed male zebrafish to two types of social interactions: (1) real opponent interactions, from which a Winner and a Loser emerged; and (2) mirror-elicited interactions, that produced individuals that did not experience a change in social status despite expressing similar levels of aggressive behavior to those of participants in real-opponent fights. Non-interacting individuals were used as a reference group. Each social phenotype (i.e. Winners, Losers, Mirror-fighters) presented a specific brain profile of nonapeptides when compared to the reference group. Moreover, the comparison between the different social phenotypes allowed to address the specific aspects of the interaction (e.g. assessment of opponent aggressive behavior vs. self-assessment of expressed aggressive behavior) that are linked with neuropeptide responses. Overall, agonistic interactions seem to be more associated with the changes in brain AVT than IT, which highlights the preferential role of AVT in the regulation of aggressive behavior already described for other species.

Structural brain connectivity and cognitive ability differences: A multivariate distance matrix regression analysis

Neuroimaging research involves analyses of huge amounts of biological data that might or might not be related with cognition. This relationship is usually approached using univariate methods, and, therefore, correction methods are mandatory for reducing false positives. Nevertheless, the probability of false negatives is also increased. Multivariate frameworks have been proposed for helping to alleviate this balance. Here we apply multivariate distance matrix regression for the simultaneous analysis of biological and cognitive data, namely, structural connections among 82 brain regions and several latent factors estimating cognitive performance. We tested whether cognitive differences predict distances among individuals regarding their connectivity pattern. Beginning with 3,321 connections among regions, the 36 edges better predicted by the individuals' cognitive scores were selected. Cognitive scores were related to connectivity distances in both the full (3,321) and reduced (36) connectivity patterns. The selected edges connect regions distributed across the entire brain and the network defined by these edges supports high-order cognitive processes such as (a) (fluid) executive control, (b) (crystallized) recognition, learning, and language processing, and (c) visuospatial processing. This multivariate study suggests that one widespread, but limited number, of regions in the human brain, supports high-level cognitive ability differences. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.

Assessing brain connectivity through electroencephalographic signal processing and modeling analysis

Brain functioning relies on the interaction of several neural populations connected through complex connectivity networks, enabling the transmission and integration of information. Recent advances in neuroimaging techniques, such as electroencephalography (EEG), have deepened our understanding of the reciprocal roles played by brain regions during cognitive processes. The underlying idea of this PhD research is that EEG-related functional connectivity (FC) changes in the brain may incorporate important neuromarkers of behavior and cognition, as well as brain disorders, even at subclinical levels. However, a complete understanding of the reliability of the wide range of existing connectivity estimation techniques is still lacking. The first part of this work addresses this limitation by employing Neural Mass Models (NMMs), which simulate EEG activity and offer a unique tool to study interconnected networks of brain regions in controlled conditions. NMMs were employed to test FC estimators like Transfer Entropy and Granger Causality in linear and nonlinear conditions. Results revealed that connectivity estimates reflect information transmission between brain regions, a quantity that can be significantly different from the connectivity strength, and that Granger causality outperforms the other estimators. A second objective of this thesis was to assess brain connectivity and network changes on EEG data reconstructed at the cortical level. Functional brain connectivity has been estimated through Granger Causality, in both temporal and spectral domains, with the following goals: a) detect task-dependent functional connectivity network changes, focusing on internal-external attention competition and fear conditioning and reversal; b) identify resting-state network alterations in a subclinical population with high autistic traits. Connectivity-based neuromarkers, compared to the canonical EEG analysis, can provide deeper insights into brain mechanisms and may drive future diagnostic methods and therapeutic interventions. However, further methodological studies are required to fully understand the accuracy and information captured by FC estimates, especially concerning nonlinear phenomena.