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Inner connections within domain of dementia praecox: role of supervisory mental processes in schizophrenia.

Kraepelin's conclusion that there were underlying common features justifying the amalgamation of catatonia, hebephrenia and paranoia hallucinatoria to form a single illness is confirmed by factor analytic studies delineating the various dimensions of schizophrenic psychopathology. Neuropsychological studies reveal that the three cardinal dimensions reflect disorder of the supervisory mental processes responsible for initiation, selection and monitoring of self-generated mental activity. Brain-imaging studies indicate that the underlying neuropathology entails disordered functional connectivity within the neural networks in multimodal association cortex that are the substrate of the supervisory mental processes, consistent with Kraepelin's own speculation about the essential nature of the condition.

Humans↗

Role of a novel photopigment, melanopsin, in behavioral adaptation to light.

Adaptation to changes in the ambient light is of critical importance to life. In mammals, three principal photoadaptation mechanisms depend on ocular photoreception and exhibit spectral sensitivity suggestive of the opsin class of photopigment(s). These include rapid adaptation of the visual system to the ambient light by pupil constriction, direct modulation of neuroendocrine function and entrainment of the circadian clock to the day:night cycle. Surprisingly, these processes can largely function independent of classical rod/cone photoreceptors, suggesting a novel opsin-based signaling mechanism. They appear to involve a recently discovered network of intrinsically photosensitive retinal ganglion cells that make direct or indirect axonal connections to brain centers regulating photoadaptive behaviors. The discovery of a novel opsin, melanopsin, in these cells has offered an exciting entry point to explore, at the molecular level, how mammals adapt to their light environment. There is now genetic proof of a principal role for melanopsin in all three major photoadaptation processes.

Adaptation, Biological↗

Diversity of inhibitory neurotransmission through GABA(A) receptors.

In the brain, highly connected and heterogeneous GABAergic cells are crucial in controling the activity of neuronal networks. They accomplish this task by communicating through remarkably diverse sets of inhibitory processes, the complexity of which is reflected by the variety of interneuron classification schemes proposed in recent years. It is now becoming clear that the subcellular localization and intrinsic properties of heteropentameric GABA(A) receptors themselves also constitute major sources of diversity in GABA-mediated signaling. This review summarizes some of the factors underlying this diversity, including GABA(A) receptor subunit composition, localization, activation, number and phosphorylation states, variance of GABA concentration in the synaptic cleft, and some of the presynaptic factors regulating GABA release.

Animals↗

Conservation and evolution of gene coexpression networks in human and chimpanzee brains.

Comparisons of gene expression between human and non-human primate brains have identified hundreds of differentially expressed genes, yet translating these lists into key functional distinctions between species has proved difficult. Here we provide a more integrated view of human brain evolution by examining the large-scale organization of gene coexpression networks in human and chimpanzee brains. We identify modules of coexpressed genes that correspond to discrete brain regions and quantify their conservation between the species. Module conservation in cerebral cortex is significantly weaker than module conservation in subcortical brain regions, revealing a striking gradient that parallels known evolutionary hierarchies. We introduce a method for identifying species-specific network connections and demonstrate how differential network connectivity can be used to identify key drivers of evolutionary change. By integrating our results with comparative genomic sequence data and estimates of protein sequence divergence rates, we confirm a number of network predictions and validate these findings. Our results provide insights into the molecular bases of primate brain organization and demonstrate the general utility of weighted gene coexpression network analysis.

Animals↗

Connectivity analysis with structural equation modelling: an example of the effects of voxel selection.

Structural equation modelling (SEM) of neuroimaging data is commonly applied to a network of distributed brain regions. We applied SEM to an fMRI dataset to identify condition-specific effects in a simple experiment composed of visual stimulation and baseline conditions. The visual network was composed of three well-defined anatomical regions (V1, V2, and V5) and three path connections (V1 --> V2, V1 --> V5, and V2 --> V5). This network was used to test four hypotheses: (1) whether the condition-specific effects for all three connections vary according to the data selected for modelling; (2) whether the "summary" measures that are often used are indeed appropriate; (3) whether measures taken from the voxel timecourse can reliably predict the condition-specific effects for each one of the three path connections, and (4) whether all voxels within an anatomical region yield equivalent SEM outcomes. There was some variability in the significance of the condition-specific effects across randomly selected voxels within regions. However, the SEM outcome from the "summary" measures was comparable to the most frequent pattern of condition-specific effects. Magnitude, delay, spread, and goodness-of-fit measures taken from a gamma fit to the voxel time courses predicted reliably the significance of the SEM condition-specific effects for each connection. This result enabled us to identify spatially coherent regions at the boundaries of V2 that displayed different condition-specific effects from those seen in the majority of the voxels. Although the generality of these results awaits further investigation, this example highlights a number of important issues for SEM. We have provided further evidence that the SEM outcome does vary somewhat according to the voxels selected and that, although the use of summary measures can give a generalised view of the connectivity pattern, they could fail to capture functional differences within specialised areas.

Adult↗

Brain-periphery connections: do they play a role in mediating the effect of centrally injected interleukin-1 beta on gonadal function?

The immune system and several endocrine axes communicate with each other through a network of molecules which collectively produce a coordinated response to immune challenges. This phenomenon, necessary for the survival of the organism, is thought to involve the release, by activated cells in the periphery, of proteins, called cytokines, which inform the brain about immune activation. The brain then organizes a series of neuroendocrine responses which participate in the regulation of the host response. With regard to the influence of cytokines on the hypothalamic-pituitary-gonadal axis, we know that the injection of these proteins lowers gonadotropin-releasing hormone release, which in turn inhibits luteinizing hormone (LH) secretion. These changes would be expected to decrease sex steroid production and, indeed, estrogens and testosterone are low in female and male rats, respectively, following acute intracerebroventricular (i.c.v.) injection of interleukin (IL)-1 beta. There is, however, another possibility that central cytokines could alter ovarian and testicular function independently of changes in gonadotropin levels. Prolonged i.c.v. infusion of the cytokine into the female rat brain produced a dramatic rise in progesterone levels. The absence of a comparable change in the progesterone release rate of males infused with IL-1 beta, and the presence of marked surges of prolactin (PRL) in the females, suggests that IL-1 beta altered ovarian function, and that the persistence of large corpora lutea induced PRL release. The possibility that the cytokine might stimulate the brain circuits that regulate PRL release, while possible, appears remote, because male rats injected with IL-1 beta showed significantly blunted PRL levels. In intact adult male rats, i.c.v. IL-1 beta administration caused the expected decrease in LH and testosterone levels, but was also accompanied by a loss of testicular responsiveness to gonadotropins. Though elevated levels of corticosteroids are known to interfere with normal gonadal steroidogenesis, blockade of IL-1-induced corticosterone release did not reverse the inhibitory influence of the cytokine. One mechanism that deserves attention is the possibility that i.c.v. injection of IL-1 beta might increase circulating cytokine levels, and indeed plasma IL-6 concentrations were significantly elevated in rats treated with IL-1 beta. This humoral mechanism may disrupt testicular function through the documented inhibitory effects of blood-borne cytokines on Leydig cell function. In addition, brain cytokines might influence a variety of peripheral events through direct (neural?) connections. This brief review discusses the hypothesis that there are brain-to-gonad connections that bypass the pituitary, and presents results that might support the possibility that central injection of IL-1 beta decreases testosterone secretion independently of blunted LH levels.

Animals↗

Patterns of hippocampal-cortical interaction dissociate temporal lobe memory subsystems.

A distributed network of brain regions supports memory retrieval in humans, but little is known about the functional interactions between areas within this system. During functional magnetic resonance imaging (fMRI), subjects retrieved real-world memories: autobiographical events, public events, autobiographical facts, and general knowledge. A common memory retrieval network was found to support all memory types. However, examination of the correlations (i.e., effective connectivity) between the activity of brain regions within the temporal lobe revealed significant changes dependent on the type of memory being retrieved. Medially, effective connectivity between the parahippocampal cortex and hippocampus increased for recollection of autobiographical events relative to other memory types. Laterally, effective connectivity between the middle temporal gyrus and temporal pole increased during retrieval of general knowledge and public events. The memory types that dissociate the common system into its subsystems correspond to those that typically distinguish between patients at initial phases of Alzheimer's disease or semantic dementia. This approach, therefore, opens the door to new lines of research into memory degeneration, capitalizing on the functional integration of different memory-involved regions. Indeed, the ability to examine interregional interactions may have important diagnostic and prognostic implications.

Adult↗

The chronoarchitecture of the cerebral cortex.

We review here a new approach to mapping the human cerebral cortex into distinct subdivisions. Unlike cytoarchitecture or traditional functional imaging, it does not rely on specific anatomical markers or functional hypotheses. Instead, we propose that the unique activity time course (ATC) of each cortical subdivision, elicited during natural conditions, acts as a temporal fingerprint that can be used to segregate cortical subdivisions, map their spatial extent, and reveal their functional and potentially anatomical connectivity. We argue that since the modular organisation of the brain and its connectivity evolved and developed in natural conditions, these are optimal for revealing its organisation. We review the concepts, methodology and first results of this approach, relying on data obtained with functional magnetic resonance imaging (fMRI) when volunteers viewed traditional stimuli or a James Bond movie. Independent component analysis (ICA) was used to identify voxels belonging to distinct functional subdivisions, based on their differential spatio-temporal fingerprints. Many more regions could be segregated during natural viewing, demonstrating that the complexity of natural stimuli leads to more differential responses in more functional modules. We demonstrate that, in a single experiment, a multitude of distinct regions can be identified across the whole brain, even within the visual cortex, including areas V1, V4 and V5. This differentiation is based entirely on the differential ATCs of different areas during natural viewing. Distinct areas can therefore be identified without any a priori hypothesis about their function or spatial location. The areas we identified corresponded anatomically across subjects, and their ATCs showed highly area-specific inter-subject correlations. Furthermore, natural conditions led to a significant de-correlation of interregional ATCs compared to rest, indicating an increase in regional specificity during natural conditions. In contrast, the correlation between ATCs of distant regions of known substantial anatomical connections increased and reflected their known anatomical connectivity pattern. We demonstrate this using the example of the language network involving Broca's and Wernicke's area and homologous areas in the two hemispheres. In conclusion, this new approach to brain mapping may not only serve to identify novel functional subdivisions, but to reveal their connectivity as well.

Brain Mapping↗

Is mood chemistry?

The chemical hypothesis of depression suggests that mood disorders are caused by a chemical imbalance in the brain, which can be corrected by antidepressant drugs. However, recent evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression, and that antidepressant drugs induce plastic changes in neuronal connectivity, which gradually lead to improvements in neuronal information processing and recovery of mood.

Affect↗

Interrogating functional connectivity of in vitro neural glia tissue model modulated through integrative control of matrix stiffness and a neurotrophic factor.

Brain function emerges from intricate cellular communication within neural networks. Both In silico neuronal models and primary neuron cells have revealed that the branching architecture of individual neurons determines the bioelectrical signal propagation pattern and dynamics. However, whether stem cell-differentiated neurons can build functional connectivity regulated by neuronal morphology has yet to be determined. Here, we hypothesized that neurite length, branching, or both factors would regulate the functional connectivity of the stem cell-differentiated neural network. We examined this hypothesis by differentiating mouse cortical neural stem cells (NSCs) on Matrigel substrates with varying storage moduli, both with and without basic fibroblast growth factor (bFGF). Interestingly, with bFGF, Matrigel with a storage modulus (G') of 100 Pa drives NSCs to differentiate into neurons with more dendritic branches, while the gel with G' of 50 Pa led to the development of longer neurites with fewer branches. Notably, branch-rich neural networks exhibited an increased frequency of calcium transients. Using a MATLAB-based analysis pipeline incorporating graph theory, we constructed spatial and temporal calcium activity maps, revealing that branching complexity, more than neurite length, correlates with the density and strength of functional neural circuits. Overall, this study demonstrates that the dendritic branching of neurons, modulated with matrix stiffness and neurotrophic factors, is a key element in enhancing the electrophysiological functionality of the stem cell-differentiated neural network. This finding will have a significant impact on efforts to reconstruct functional neural tissue models, advancing both regenerative therapies and unexplored applications, including biological computing.

Animals↗

Effects of olanzapine on cerebellar functional connectivity in schizophrenia measured by fMRI during a simple motor task.

BACKGROUND: According to current theories, schizophrenia results from altered connectivity in brain circuits for fundamental cognitive operations. Consequently, the poorly understood mechanisms of neuroleptic treatment may be explainable by altered functional interactions within such networks. The 'cognitive dysmetria' model hypothesizes that one key structure in these circuits is the cerebellum. To investigate the effects of olanzapine on cerebellar functional connectivity (CFC), a seed-voxel correlation analysis (SVCA) was used in a functional magnetic resonance imaging (fMRI) study of a simple finger-tapping task. METHODS: fMRI scans were obtained from six schizophrenic patients under both drug-free and olanzapine-treated conditions and from a matched control group of six healthy subjects at corresponding time points. SVCAs were performed for anatomically and functionally standardized seed voxels in the anterior cerebellum. SVCA results were then processed by three different randomization analyses. RESULTS: The analyses revealed that olanzapine caused widespread changes of CFC, including prominent changes in prefrontal cortex and mediodorsal thalamus. Significant changes in motor structures were found after subtractions within both groups and may thus indicate repetition effects rather than drug effects. Olanzapine 'normalized' the patients' CFC patterns for the right, but not for the left cerebellum. CONCLUSION: Even for a simple motor task, olanzapine affects functional interactions between the cerebellum and many non-motor brain regions, including elements of the 'cognitive dysmetria' circuit. Altogether, our findings suggest that olanzapine has a stronger differential effect on neural activity in prefrontal cortex and thalamus than in motor structures.

Adult↗

Do cortical maps depend on the timing of sensory input? Experimental evidence and computational model.

Fast adaptations in the functional organization of primary sensory cortex are generally assumed to result from changes of network connectivity. However, the effects of intrinsic neuronal excitability alterations due to the activation of neighboring cortical representational zones, which might as well account for the changes of cortical representative maps, have been paid little attention to. In a recent experiment (Braun et al. 2000b) we showed by neuromagnetic source imaging that random or fixed sequence stimulation of three digits of both hands led to stimulation-timing-induced changes in primary somatosensory (SI) cortical maps. The distance between the cortical representation of thumb and middle finger became significantly shorter during the fixed sequence stimulation. The analysis on the time course of the cortical map changes revealed that these reorganizations occurred within minutes and were fully reversible. The previously reported results were interpreted as the involvement of a superordinate center responsible for detecting and activating the appropriate maps. Here we present an alternative parsimonious explanation that is supported by a computational model. Based on the experimental evidence, we developed a simple model that took intrinsic neuronal excitability together with subthreshold activation into account and assumed partial cortical overlap of the representational zones of neighboring digits. Furthermore, in the model the neuronal excitability decayed slowly with respect to the stimulation frequency. The observed cortical map changes in the experiment could be reproduced by the two-layer feed-forward computational network. Our model thus suggests that the dynamic shifts of cortical maps can be explained by the state and time course of intrinsic neuronal excitability and subthreshold activation, without involving changes in network connectivity.

Adult↗

Oscillatory network with self-organized dynamical connections for synchronization-based image segmentation.

An oscillatory network of columnar architecture located in 3D spatial lattice was recently designed by the authors as oscillatory model of the brain visual cortex. Single network oscillator is a relaxational neural oscillator with internal dynamics tunable by visual image characteristics - local brightness and elementary bar orientation. It is able to demonstrate either activity state (stable undamped oscillations) or "silence" (quickly damped oscillations). Self-organized nonlocal dynamical connections of oscillators depend on oscillator activity levels and orientations of cortical receptive fields. Network performance consists in transfer into a state of clusterized synchronization. At current stage grey-level image segmentation tasks are carried out by 2D oscillatory network, obtained as a limit version of the source model. Due to supplemented network coupling strength control the 2D reduced network provides synchronization-based image segmentation. New results on segmentation of brightness and texture images presented in the paper demonstrate accurate network performance and informative visualization of segmentation results, inherent in the model.

Animals↗

Logistic patterning of brain activity.

Brain activity is a set of electrochemical events in the neural tissue during a specified period of time. Neural networks are the functionally connected and dynamically organized population of neurons and neuroglial cells, serving as a unified interface between environmental input and behavioral output at a specified time. They are patterned dynamically in neural space, time and intensity. It is proposed that 1. the electrophysiological patterning of brain activity follows the laws of logistic growth, decay and impulse response function and 2. that this process of logistic transform (LOGIT) of electrochemical processes is itself the general code of information transfer in the brain. A mathematical model of logistic transformation and new electrophysiological data based on the topographic mapping of event-related potentials (ERP) during selective auditory attentional tasks from nine healthy adults is presented. The N100-P200 and the N200-P300 segments of ERP's were analyzed at 20 ms intervals. Logarithmic latencies and voltages were highly correlated. Significant correlation was found between the mathematically estimated and actual values. The interpeak latencies also followed the logistic growth pattern and could be predicted by the model. A general equation of logistic transformation of brain activity, including variables of cortical voltage and frequency is proposed.

Adult↗

VIP- and PACAP-mediated immunomodulation as prospective therapeutic tools.

The immune system and the brain continuously signal to each other, often along the same pathways, which might explain the connection between immunity, the brain and disease. Neuropeptides and their receptors represent part of this communication network, and recent work has examined their relevance to health, proving a potentially crucial clinical significance. The structurally related neuropeptides, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP), are emerging as a means of fine tuning in the maintenance a balanced steady state in the immune system. Murine knockout and transgenic models for a VIP receptor suggest that VIP is an endogenous anti-inflammatory mediator with characteristics resembling those of a T-helper-2 cytokine. Thus, through molecular mechanisms that are being discovered, VIP might extend the range of therapeutic treatments available for various disorders, including acute and chronic inflammatory diseases, septic shock and autoimmune diseases.

Adjuvants, Immunologic↗

[A new history of basal ganglia and physiopathology of Parkinson's disease].

The author analyzes basic and clinical experimental works of the last forty years and reaches the following conclusions: The motor system is an indivisible entity in which the basal ganglia are a key part. An important link in the history of the basal ganglia is the description by Llamas and Reinoso-Suárez in 1965 of connections from the substantia nigra compacta to the globus pallidus medialis and lateralis, and striatum through extremely thin, diffusely distributed fibers. They also described connections from the ventral tegmental area to the basal forebrain and the cerebral cortex. These connections are still not accepted one decade later. Rather than as cortico-basal ganglia-cortical parallel loops, the basal ganglia are actually structured as a widely distributed neuronal network with a great biochemical and connective variety. Basal ganglia intrinsic circuits have an important influential role in this network. Very varied brain structures influence basal ganglia neuronal network, mainly the cerebral cortex and the thalamic nuclei, essentially those that receive output from the basal ganglia. This complex organization provides the foundations for and elucidates the difficulty of explaining the pathophysiology of the clinical manifestations of Parkinson's disease as well as illustrating the need for future multidisciplinary research on this topic.

Basal Ganglia↗

Development of a three-dimensional multiscale agent-based tumor model: simulating gene-protein interaction profiles, cell phenotypes and multicellular patterns in brain cancer.

Experimental evidence suggests that epidermal growth factor receptor (EGFR)-mediated activation of the signaling protein phospholipase Cgamma plays a critical role in a cancer cell's phenotypic decision to either proliferate or to migrate at a given point in time. Here, we present a novel three-dimensional multiscale agent-based model to simulate this cellular decision process in the context of a virtual brain tumor. Each tumor cell is equipped with an EGFR gene-protein interaction network module that also connects to a simplified cell cycle description. The simulation results show that over time proliferative and migratory cell populations not only oscillate but also directly impact the spatio-temporal expansion patterns of the entire cancer system. The percentage change in the concentration of the sub-cellular interaction network's molecular components fluctuates, and, for the 'proliferation-to-migration' switch we find that the phenotype triggering molecular profile to some degree varies as the tumor system grows and the microenvironment changes. We discuss potential implications of these findings for experimental and clinical cancer research.

Apoptosis↗

Functional magnetic resonance imaging and cognition at the very early stage of MS.

Dysfunction of high controlled information processing is present in patients with multiple sclerosis (MS) right at the beginning of the disease. One hypothesis is that disruption of communication inside large-scale cortical networks, occurring as a consequence of white matter damage, may constitute the anatomical substrate of cognitive impairment at the very early stage of MS. Disturbance of interregional synchronization might be the main pathogenic factor in controlled information processing deficiency in early MS. Preliminary functional MRI studies (fMRI) have provided important clues to corroborate the connectivity hypotheses. First, brain connectivity assessed by fMRI has brought new data about the influence of diffuse white matter damage on connectivity efficiency inside large-scale networks. These studies have suggested that connectivity disturbances occur inside the working memory network in patients at the very early stage of MS and appear related to the extent of structural white matter damage. Also, fMRI studies have suggested that patients may partially compensate for connectivity impairment by a greater cognitive control. Such a compensatory mechanism could limit the determinant functional impact of diffuse white matter damage on high controlled information processing.

Age of Onset↗