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PubMed2005

Slow endogenous activity transients and developmental expression of K+-Cl- cotransporter 2 in the immature human cortex.

Spontaneous transients of correlated activity are a characteristic feature of immature brain structures, where they are thought to be crucial for the establishment of precise neuronal connectivity. Studies on experimental animals have shown that this kind of early activity in cortical structures is composed of long-lasting, intermittent network events, which undergo a developmental decline that is closely paralleled by the maturation of GABAergic inhibition. In order to examine whether similar events occur in the immature human cortex, we performed direct current-coupled electroencephalography (EEG) recordings from sleeping preterm babies. We show now that much of the preterm EEG activity is confined to spontaneous, slow activity transients. These transients are characterized by a large voltage deflection that nests prominent oscillatory activity in several frequency bands covering the whole frequency spectrum of the preterm EEG (<0.1-30 Hz). The slow voltage deflections had an amplitude of up to 800 microV. Most of these 'giant' events originated in the temporo-occipital areas, with a maximum rate of about 8/min, and their occurrence as well as amplitude showed a decline by the time of normal birth. In age-matched fetal brain tissue, this decrease in the spontaneous activity transients was associated with a developmental up-regulation of the neuronal chloride extruder K+-Cl- cotransporter 2, a crucial molecule for the generation of inhibitory GABAergic Cl- currents. Our work indicates that slow endogenous activity transients in the immature human neocortex are mostly confined to the prenatal stage and appear to be terminated in parallel with the maturation of functional GABAergic inhibition.

Cerebral Cortex↗
PubMed1998

Neural systems for control of voluntary action--a hypothesis.

Action is the means by which we and animals survive. It consists of a complex combination of movements which are either innately endowed or acquired by learning. In this article, I propose a hypothesis on the relationship between the organization of action and the organization of the brain. Innate and learned actions are controlled by different levels of neural networks: innate actions are controlled by reflex mechanisms and pattern generators in the spinal cord and brainstem, while learned actions are controlled by the cerebral cortex, basal ganglia, and cerebellum. However, these mechanisms are by no means independent. Phylogenetically, animals have acquired progressively more complex actions by gaining neural connections between different neural mechanisms. This is accomplished by the connection from newly evolving brain structures, particularly the cerebral cortex, to reflex or pattern generator mechanisms, as typically observed in the neural mechanism for saccadic eye movement. The cerebral cortex is a general purpose device which can be used in different ways depending on biological demands; in other words, it is used for learned actions. In consequence, a given movement (e.g., saccade) can be produced by different neural circuits, all converging onto the movement generation mechanism (e.g., s.c.) in an excitatory manner. However, such converging inputs that promote actions are likely to produce a chaotic explosion of neural signals. There must be some way to prevent the explosion and select signals that are most appropriate for the current behavioral context. The basal ganglia system evolved to accomplish this goal. It exerts a powerful inhibition on its targets in the brainstem (e.g., s.c.) and the thalamo-cortical system, thereby closing the gate for the action-promoting excitatory inputs; it also removes the sustained inhibition using another inhibition originating in the striatum (input structure of the basal ganglia), thereby opening the gate so that an appropriate action is executed. There are at least two additional functions of the basal ganglia. First, the selection mechanism of the basal ganglia is used also for the selection of simulated actions (e.g., thoughts) which are largely controlled by the association cortices. Second, it is used for learning of behavioral procedures: various kinds of signals from the cerebral cortex converge onto neurons in the basal ganglia to generate temporary association of neural signals, whose behavioral significance is evaluated by signals from the limbic system via dopaminergic neurons. The procedural memories thus created (perhaps in the cerebral cortex, particularly premotor cortices) are then used to guide learning of individual movements in which the cerebellum plays a crucial role. Thus, the implementation of learned actions is carried out by two distinct neural systems, each forming a loop circuit: 1) cerebral cortex and basal ganglia; 2) cerebral cortex and cerebellum. Although these neural systems are independent structurally, they work in parallel and cooperatively to acquire and execute learned procedures (actions).

Brain↗
PubMed1999

Parkinsonian tremor and simplification in network dynamics.

We explore the behavior of richly connected inhibitory neural networks under parameter changes that correspond to weakening of synaptic efficacies between network units, and show that transitions from irregular to periodic dynamics are common in such systems. The weakening of these connections leads to a reduction in the number of units that effectively drive the dynamics and thus to simpler behavior. We hypothesize that the multiple interconnecting loops of the brain's motor circuitry, which involve many inhibitory connections, exhibit such transitions. Normal physiological tremor is irregular while other forms of tremor show more regular oscillations. Tremor in Parkinson's disease, for example, stems from weakened synaptic efficacies of dopaminergic neurons in the nigro-striatal pathway, as in our general model. The multiplicity of structures involved in the production of symptoms in Parkinson's disease and the reversibility of symptoms by pharmacological and surgical manipulation of connection parameters suggest that such a neural network model is appropriate. Furthermore, fixed points that can occur in the network models are suggestive of akinesia in Parkinson's disease. This model is consistent with the view that normal physiological systems can be regulated by robust and richly connected feedback networks with complex dynamics, and that loss of complexity in the feedback structure due to disease leads to more orderly behavior.

Humans↗
PubMed1998

Neural network classifications and correlation analysis of EEG and MEG activity accompanying spontaneous reversals of the Necker cube.

It has recently been suggested that reentrant connections are essential in systems that process complex information [A. Damasio, H. Damasio, Cortical systems for the retrieval of concrete knowledge: the convergence zone framework, in: C. Koch, J.L. Davis (Eds.), Large Scale Neuronal Theories of the Brain, The MIT Press, Cambridge, 1995, pp. 61-74; G. Edelman, The Remembered Present, Basic Books, New York, 1989; M.I. Posner, M. Rothbart, Constructing neuronal theories of mind, in: C. Koch, J.L. Davis (Eds.), Large Scale Neuronal Theories of the Brain, The MIT Press, Cambridge, 1995, pp. 183-199; C. von der Malsburg, W. Schneider, A neuronal cocktail party processor, Biol. Cybem., 54 (1986) 29-40]. Reentry is not feedback, but parallel signalling in the time domain between spatially distributed maps, similar to a process of correlation between distributed systems. Accordingly, it was expected that during spontaneous reversals of the Necker cube, complex patterns of correlations between distributed systems would be present in the cortex. The present study included EEG (n=4) and MEG recordings (n=5). Two experimental questions were posed: (1) Can distributed cortical patterns present during perceptual reversals be classified differently using a generalised regression neural network (GRNN) compared to processing of a two-dimensional figure? (2) Does correlated cortical activity increase significantly during perception of a Necker cube reversal? One-second duration single trials of EEG and MEG data were analysed using the GRNN. Electrode/sensor pairings based on cortico-cortical connections were selected to assess correlated activity in each condition. The GRNN significantly classified single trials recorded during Necker cube reversals as different from single trials recorded during perception of a two-dimensional figure for both EEG and MEG. In addition, correlated cortical activity increased significantly in the Necker cube reversal condition for EEG and MEG compared to the perception of a non-reversing stimulus. Coherent MEG activity observed over occipital, parietal and temporal regions is believed to represent neural systems related to the perception of Necker cube reversals.

Adolescent↗
PubMed1982

Connections of the amygdala of the rat. IV: Corticoamygdaloid and intraamygdaloid connections as studied with axonal transport of horseradish peroxidase.

The corticoamygdaloid and intraamygdaloid projections of the rat were studied by the use of retrograde transport of horseradish peroxidase (HRP). Observations based on anterograde transport of the enzyme were exploited to determine the course of the intrinsic connections. The HRP was injected stereotactically by means of iontophoresis. Most of the amygdaloid nuclei were selectively injected, and all but a few were reached by more than one approach. The vast majority of corticoamygdaloid fibers was found to originate in cortical areas defined as allocortical (Stephan, '75). From the medial frontal cortex the central amygdaloid nucleus (AC) receives a hitherto undescribed projection originating in the tenia tecta; and both the AC and the lateral amygdaloid nucleus (AL) receive fibers from the prelimbic and infralimbic areas. The anterior cingulate area entertains a weak connection with the basolateral amygdaloid nucleus (BL). As to the insular cortex, the posterior agranular insular area projects to all amygdaloid subdivisions; the BL, AC, and the anterior cortical nucleus (COa) receive, in addition, fibers from the ventral agranular area. The prepyriform cortex connects with the entire amygdala except the medial nucleus (Am). The amygdala receives afferents from a transitional area between the amygdala and the entorhinal area. The entorhinal area proper is related to the amygdala via projections from the ventral part of the lateral entorhinal area to the AL and from the dorsal part of the lateral entorhinal area to the BL. The former nucleus also receives fibers from the perirhinal region. Additional amygdalopetal connections from the hippocampal region include a previously undescribed projection from the temporal two-thirds of CA1 to the AL and BL and to the posterior cortical nucleus (COp) with the adjacent periamygdaloid cortex (PAC). The subiculum projections to the AL, and more modestly to other amygdaloid nuclei. There is an extensive network of intraamygdaloid connections, the Am and AC being the only nuclei not giving rise to the intrinsic fibers.

Amygdala↗
PubMed2005

Comparing functional connectivity via thresholding correlations and singular value decomposition.

We compare two common methods for detecting functional connectivity: thresholding correlations and singular value decomposition (SVD). We find that thresholding correlations are better at detecting focal regions of correlated voxels, whereas SVD is better at detecting extensive regions of correlated voxels. We apply these results to resting state networks in an fMRI dataset to look for connectivity in cortical thickness.

Brain↗
PubMed2004

Dynamical motifs: building blocks of complex dynamics in sparsely connected random networks.

Spatiotemporal network dynamics is an emergent property of many complex systems that remains poorly understood. We suggest a new approach to its study based on the analysis of dynamical motifs-small subnetworks with periodic and chaotic dynamics. We simulate randomly connected neural networks and, with increasing density of connections, observe the transition from quiescence to periodic and chaotic dynamics. This transition is explained by the appearance of dynamical motifs in the structure of these networks. We also observe domination of periodic dynamics in simulations of spatially distributed networks with local connectivity and explain it by the absence of chaotic and the presence of periodic motifs in their structure.

Brain↗
PubMed2003

Measuring information integration.

BACKGROUND: To understand the functioning of distributed networks such as the brain, it is important to characterize their ability to integrate information. The paper considers a measure based on effective information, a quantity capturing all causal interactions that can occur between two parts of a system. RESULTS: The capacity to integrate information, or Phi, is given by the minimum amount of effective information that can be exchanged between two complementary parts of a subset. It is shown that this measure can be used to identify the subsets of a system that can integrate information, or complexes. The analysis is applied to idealized neural systems that differ in the organization of their connections. The results indicate that Phi is maximized by having each element develop a different connection pattern with the rest of the complex (functional specialization) while ensuring that a large amount of information can be exchanged across any bipartition of the network (functional integration). CONCLUSION: Based on this analysis, the connectional organization of certain neural architectures, such as the thalamocortical system, are well suited to information integration, while that of others, such as the cerebellum, are not, with significant functional consequences. The proposed analysis of information integration should be applicable to other systems and networks.

Brain↗
PubMed1999

[What to expect from MRi in the investigation of the central nervous system?].

Functional Magnetic Resonance Imaging (fMRI) has appeared as a new tool which is very powerful for cognitive neuroscience, offering the potential to look at the dynamics of cerebral processes underlying cognition, noninvasively and on an individual basis. Work remains to be done to optimize the technique and to better understand its basic mechanisms, but one may expect to build in a few years a functional list of the brain cortical networks of regions implicated in sensory-motor or cognitive processes. Still, the real understanding of brain function requires direct access to the functional unit made of the neuron, so that one may look at the transient temporal relationships that exist between largely distributed groups of hundreds or thousands of neurons. Furthermore, communication pathways between networks must be identified to establish connectivity maps at the individual scale, taking into account individual variability resulting from genetic factors and cerebral plasticity. In this respect, MRI of molecular diffusion is very sensitive to water molecular motion and, thus, to tissue dynamic microstructure, such as cell geometry. Preliminary data suggest that diffusion MRI visualizes dynamic tissue changes associated with large neuronal activation and space orientation of large bundles of myelinated axons in the white matter.

Brain Ischemia↗
PubMed1987

Scanning electron microscopic investigation of mouse cerebellar macrophages in vitro.

Dispersed monolayer cultures of post-natal mouse cerebella were studied using scanning electron microscopy. Special attention was given to the morphology of the brain macrophages and their interaction with neuronal cells. The brain macrophages resemble other macrophages and mononuclear phagocytes in vitro, reported in the literature. Their ability to induce neuronal growth cones to avoid contact, results in areas devoid of neuronal processes (halos) in this culture system; this seems of considerable interest in connection with their possible developmental role in post-natal reshaping of the brain. Scanning electron microscope observations indicate that these halos are not the result of phagolysis of already established neuronal networks, but can only be induced during neuronal growth and process formation. Established, intact neurons are apparently not altered or harmed by contact with brain macrophages.

Animals↗
PubMed2004

Brain differences in newborn rats predisposed to helpless and depressive behavior.

Inborn brain differences in metabolic capacity were mapped in congenitally helpless rats, a genetically selected strain predisposed to show helpless and depressive behavior. There are a number of brain regions showing abnormal metabolism in adult congenitally helpless rats. Some of these alterations may be innate while others may be due to environmental factors, such as maternal care and postnatal stress. To identify which brain structures show innate differences, brains of newborn rats from congenitally helpless and non-helpless strains were compared using cytochrome oxidase histochemistry, an endogenous marker of regional metabolic capacity. A smaller subset of regions affected in adults showed significantly less metabolic activity in the newborn brains, including paraventricular hypothalamus, habenula, hippocampus, subiculum, lateral septal nucleus, anterior cingulate cortex, infralimbic cortex, and medial orbitofrontal cortex. A covariance analysis further revealed a striking reduction of functional connectivity in the congenitally helpless brain, including a complete decoupling of limbic forebrain regions from midbrain/diencephalic regions. This pattern of brain metabolism suggests that helplessness vulnerability is linked to altered functioning of limbic networks that are key to controlling the hypothalamic-pituitary-adrenal axis. This implies that vulnerable animals have innate deficits in brain systems that would normally allow them to cope with stress, predisposing them in this manner to more readily develop helpless and depressive behaviors.

Analysis of Variance↗
PubMed2001

Mind blindness and the brain in autism.

Experimental evidence shows that the inability to attribute mental states, such as desires and beliefs, to self and others (mentalizing) explains the social and communication impairments of individuals with autism. Brain imaging studies in normal volunteers highlight a circumscribed network that is active during mentalizing and links medial prefrontal regions with posterior superior temporal sulcus and temporal poles. The brain abnormality that results in mentalizing failure in autism may involve weak connections between components of this system.

Autistic Disorder↗
PubMed2001

The effects of bilateral hippocampal damage on fMRI regional activations and interactions during memory retrieval.

Using functional magnetic resonance imaging (fMRI) we examined successful retrieval of real-world memories in a patient (Jon) with selective bilateral hippocampal pathology resulting from perinatal hypoxia compared with healthy control subjects. Jon activated the same brain regions during memory retrieval as control subjects, both medial and lateral on the left. In contrast to controls, Jon also activated many homologous regions on the right. In spite of having 50% volume loss bilaterally in his hippocampi, retrieval in Jon was associated with increased activation of the hippocampi. Furthermore, hippocampal activity, as with the controls, was differential, being most responsive to retrieval of autobiographical events compared with other memory types (autobiographical facts, public events, general knowledge). Jon made a distinction between events that the control subjects did not make, namely that some of the autobiographical and public events he clearly remembered, while others he found that he knew about but did not truly remember. His hippocampi and medial frontal cortex were significantly more active during retrieval of events for which he had clear and conscious recollection compared with those he knew as much about, including the context, but could not remember experiencing. Although Jon activates the same network of brain regions as the controls (albeit bilaterally), and with the same pattern of response in the hippocampus, the communication between regions differs from controls with regard to hippocampal-cortical connectivity. In controls there was increased effective connectivity between parahippocampal cortex and hippocampus, specifically during the retrieval of autobiographical events. In contrast, this increase was not apparent in Jon; rather, retrieval of autobiographical events elicited greater interaction between the hippocampus and retrosplenial cortex, and also increased interaction between retrosplenial and medial frontal cortex. This study underlines the value of scanning patients using fMRI while they undertake tasks they can perform, in this case allowing us to confirm the functionality of remaining tissue in the damaged hippocampi, and to appreciate the neural basis of a distinction (remember/know) that control subjects do not make. Besides refining our knowledge of the hippocampal role in autobiographical event memory, this study indicates that recruitment of bilateral regions during memory retrieval, and altered patterns of effective connectivity between brain regions may be important indicators of disordered memory.

Adult↗
PubMed2003

Topology and computational performance of attractor neural networks.

To explore the relation between network structure and function, we studied the computational performance of Hopfield-type attractor neural nets with regular lattice, random, small-world, and scale-free topologies. The random configuration is the most efficient for storage and retrieval of patterns by the network as a whole. However, in the scale-free case retrieval errors are not distributed uniformly among the nodes. The portion of a pattern encoded by the subset of highly connected nodes is more robust and efficiently recognized than the rest of the pattern. The scale-free network thus achieves a very strong partial recognition. The implications of these findings for brain function and social dynamics are suggestive.

Journal Article↗
PubMed2006

White matter damage on diffusion tensor imaging correlates with age-related cognitive decline.

BACKGROUND: Damage to white matter tracts, resulting in "cerebral disconnection," may underlie age-related cognitive decline. METHODS: Using diffusion tensor MRI (DTI) to investigate white matter damage, and magnetic resonance spectroscopy (MRS) to look at its underlying pathologic basis, the authors investigated the relationship between white matter structure and cognition in 106 healthy middle-aged and elderly adults. Fractional anisotropy (FA) and mean diffusivity (MD) values, whole brain white matter histograms, and regions of interest placed in the white matter of the centrum semiovale were analyzed. Correlations with executive function, working memory, and information-processing speed were performed. RESULTS: There was a progressive reduction in FA and increase in diffusivity with age in both region of interest (r = 0.551, p < 0.001), and whole brain histograms (r = 0.625, p < 0.001). DTI values correlated with performance in all three cognitive domains. After controlling for age, DTI parameters correlated with working memory but not with the other two cognitive domains. MRS studies found a correlation of N-acetyl aspartate, a neuronal marker, with DTI parameters (r = 0.253, p < 0.05). CONCLUSION: The results are consistent with white matter damage due to axonal loss, causing age- related cognitive decline. Working memory may be particularly dependent on complex networks dependent on white matter connections.

Aged↗
PubMed1998

The behavioral neurology of cerebral white matter.

Behavioral neurology has primarily focused on brain-behavior relations as revealed by disorders of the cerebral cortex and subcortical gray matter. Disorders of cerebral white matter have received less attention. This article considers the contribution of cerebral white matter to normal behavioral function and the effects of white matter disorders on behavior. Diffuse dysfunction is more common than focal impairment, and the term white matter dementia has been proposed as a clinical entity. Conventional neuroimaging has enabled more accurate identification of white matter regions participating in neurobehavioral operations, and newer imaging techniques may define white matter connectivity within and between the hemispheres. As an essential component of neural networks, cerebral white matter contributes to cognitive and emotional functions, and lesions of white matter disconnect these networks to produce neurobehavioral syndromes.

Behavior↗
PubMed2004

Habenular and interpeduncularis nuclei: shared components in multiple-function networks.

This paper reviews habenula (Hb) and interpeduncularis nucleus (IPN) literature from the perspective that the axial anatomy of Hb-IPN could be shared by numerous brain circuits that subserve diverse functions. The first section summarizes the major anatomical connections, showing that the axis is strategically positioned between key rostral structures and brainstem areas. Little is known about these connections as they relate to the heterogeneous Hb-IPN sub-nuclei. Insufficient understanding exists about ascending pathways in the fasiculus retroflexus, possible pineal gland connections with the Hb, serotonergic inputs, whether given pathways are excitatory or inhibitory, and interactions of neurotransmitter systems. Next reviewed are studies that implicate the Hb-IPN axis in a variety of brain functions and behaviors. These include nociception, learning and memory, motor activity, sexual and maternal behavior, stress, affective states (anxiety, depression, and reward phenomena), sleep, and eating and drinking behavior. I propose that these multiple functions arise because the Hb-IPN is a shared-component axis in the multiple circuits that subserve these different elements of behavior. More research is needed to test the possibility that the Hb-IPN provides a way for the brain to share circuitry, to explore the significance of the anatomical convergence of inputs to the lateral Hb, to map the circuitry of the subnuclei in Hb and IPN, to explore the interactions of the multiple neurotransmitter systems involved, to conduct studies in simpler animals, and to design experiments that will elucidate system properties of circuits that share the Hb-IPN axis.

Animals↗
PubMed2004

[Molecular mechanisms of neuronal connective tissue genesis during the course of cerebral cortex development].

The cerebral cortex constitutes one of the most complex structures in our brain. In correlation with its elaborate functions, it is characterized by the great complexity of its neuronal connections, but the mechanisms responsible for the generation of these connections remain poorly known. We have recently initiated the characterization of a new multigenic family of axon guidance factors, the ephrin/Eph gene family, during the development of neuronal connections in the mouse cortex. Combining expression studies, in vitro guidance essays, and in vivo analysis of mutant mice, enabled us to demonstrate the critical role of ephrin/Eph genes in the development of cortical networks. Mutant mice for ephrin/Eph genes display a topographic distortion of their cortical somatosensory map, as well as ectopic projections from the motor thalamus to the somatosensory cortex. The identification of factors like ephrins, capable to (re)specify the pattern of neuronal connections, has implications for our understanding of pathological brain development (epilepsy, abnormal movements, psychiatric diseases), and in the perspective of the rational design of cell therapies of neurodegenerative diseases.

Animals↗