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Visual binding through reentrant connectivity and dynamic synchronization in a brain-based device.

Effective visual object recognition requires mechanisms to bind object features (e.g. color, shape and motion) while distinguishing distinct objects. Synchronously active neuronal circuits among reentrantly connected cortical areas may provide a basis for visual binding. To assess the potential of this mechanism, we have constructed a mobile brain-based device, Darwin VIII, which is guided by simulated analogues of cortical and sub-cortical areas required for visual processing, decision-making, reward and motor responses. These simulated areas are reentrantly connected and each area contains neuronal units representing both the mean activity level and the relative timing of the activity of groups of neurons. Darwin VIII learns to discriminate among multiple objects with shared visual features and associates 'target' objects with innately preferred auditory cues. We observed the co-activation of globally distributed neuronal circuits that corresponded to distinct objects in Darwin VIII's visual field. These circuits, which are constrained by a reentrant neuroanatomy and modulated by behavior and synaptic plasticity, are necessary for successful discrimination. By situating Darwin VIII in a rich real-world environment involving continual changes in the size and location of visual stimuli due to self-generated movement, and by recording its behavioral and neuronal responses in detail, we were able to show that reentrant connectivity and dynamic synchronization provide an effective mechanism for binding the features of visual objects.

Acoustic Stimulation↗

Suppression of synaptic transmission may allow combination of associative feedback and self-organizing feedforward connections in the neocortex.

Selective suppression of synaptic transmission during learning is proposed as a physiological mechanism for combining associative memory function at feedback synapses with self-organization of feedforward synapses in neocortical structures. A computational model demonstrates how selective suppression of feedback transmission allows this combination of synaptic function. During learning, sensory stimuli and the desired response are simultaneously presented as input to the network. Feedforward connections form self-organized representations of input, while suppressed feedback connections learn the transpose of the feedforward connectivity. During recall, suppression of transmission is removed, input activates the self-organized representation, and activity settles into a learned solution to the problem. This computational model can be used for learning of problems which are not linearly separable, including the negative patterning task (the XOR problem). Experiments in brain slice preparations of the rat somatosensory cortex tested whether the combination of self-organization and associative memory function could be provided by cholinergic suppression selective for feedback versus feedforward synapses. The cholinergic agonist carbachol selectively suppressed synaptic potentials elicited by stimulation of layer I (which contains a high percentage of feedback synapses), while having no effect on synaptic potentials elicited by stimulation of layer IV (with a high percentage of afferent and feedforward synapses).

Animals↗

The rises and falls of disconnection syndromes.

In a brain composed of localized but connected specialized areas, disconnection leads to dysfunction. This simple formulation underlay a range of 19th century neurological disorders, referred to collectively as disconnection syndromes. Although disconnectionism fell out of favour with the move against localized brain theories in the early 20th century, in 1965, an American neurologist brought disconnection to the fore once more in a paper entitled, 'Disconnexion syndromes in animals and man'. In what was to become the manifesto of behavioural neurology, Norman Geschwind outlined a pure disconnectionist framework which revolutionized both clinical neurology and the neurosciences in general. For him, disconnection syndromes were higher function deficits that resulted from white matter lesions or lesions of the association cortices, the latter acting as relay stations between primary motor, sensory and limbic areas. From a clinical perspective, the work reawakened interest in single case studies by providing a useful framework for correlating lesion locations with clinical deficits. In the neurosciences, it helped develop contemporary distributed network and connectionist theories of brain function. Geschwind's general disconnectionist paradigm ruled clinical neurology for 20 years but in the late 1980s, with the re-emergence of specialized functional roles for association cortex, the orbit of its remit began to diminish and it became incorporated into more general models of higher dysfunction. By the 1990s, textbooks of neurology were devoting only a few pages to classical disconnection theory. Today, new techniques to study connections in the living human brain allow us, for the first time, to test the classical formulation directly and broaden it beyond disconnections to include disorders of hyperconnectivity. In this review, on the 40th anniversary of Geschwind's publication, we describe the changing fortunes of disconnection theory and adapt the general framework that evolved from it to encompass the entire spectrum of higher function disorders in neurology and psychiatry.

Agnosia↗

Modulating neural networks with transcranial magnetic stimulation applied over the dorsal premotor and primary motor cortices.

Our study uses the combined transcranial magnetic stimulation/positron emission tomography (TMS/PET) method for elucidating neural connectivity of the human motor system. We first altered motor excitability by applying low-frequency repetitive TMS over two cortical motor regions in separate experiments: the dorsal premotor and primary motor cortices. We then assessed the consequences of modulating motor excitability by applying single-pulse TMS over the primary motor cortex and measuring: 1) muscle responses with electromyography and 2) cerebral blood flow with PET. Low-frequency repetitive stimulation reduced muscle responses to a similar degree in both experiments. To map networks of brain regions in which activity changes reflected modulation of motor excitability, we generated t-statistical maps of correlations between reductions in muscle response and differences in cerebral blood flow. Low-frequency repetitive stimulation altered neural activity differently in both experiments. Neural modulation occurred in multiple brain regions after dorsal premotor cortex stimulation; these included motor regions in the frontal cortex as well as more associational regions in the parietal and prefrontal cortices. In contrast, neural modulation occurred in a smaller number of brain regions after primary motor cortex stimulation, many of these confined to the motor system. These findings are consistent with the known differences between the dorsal premotor and primary motor cortices in the extent of cortico-cortical anatomical connectivity in the monkey.

Adult↗

Regional brain variations of cytochrome oxidase activity in spontaneously hypertensive mice.

To explore the central disturbances resulting from blood pressure changes, spontaneously hypertensive mice (SHM) were compared to normotensive controls for cytochrome oxidase (CO) activity, an index of oxidative capacity in the central nervous system and a marker of long-term regional brain metabolism and neuronal activity. In all brain areas presenting significant enzymatic variations, only increases in CO activity were found in SHM, particularly the central autonomic network. However, only specific regions were affected, namely the insular cortex and the hypothalamic nuclei principally involved in high-order autonomic control. Altered limbic structures included the lateral septum, various hippocampal subregions, as well as prelimbic cortex. CO activity was also elevated in several forebrain regions, including those directly connected to the limbic system, such as the nucleus accumbens, the claustrum, and dorsomedial and reticular thalamic nuclei, as well as subthalamic and ventrolateral thalamic nuclei. In the brainstem, the only regions affected were the locus coeruleus, site of noradrenergic cell bodies, the trigeminal system, and four interconnected regions: the inferior colliculus, the paramedial reticular formation, the medial vestibular, and the cerebellar fastigial nuclei. These data show that specific regions modulating sympathetic nerve discharge are activated in young adult SHM, possibly due to mitochondrial dysfunction and excitotoxicity.

Animals↗

Thalamocortical connections of rat posterior parietal cortex.

The neuronal connections of rat posterior parietal cortex (PPC) have been examined using retrograde fluorescent axonal tracers. We have found that PPC receives thalamic input predominantly from the lateral posterior and lateral dorsal nuclei, and not from the ventrobasal nucleus, which projects to the rostrally adjacent hindlimb cortex, or from the dorsal lateral geniculate nucleus, which projects to the caudally adjacent visual association area. PPC has reciprocal corticocortical connections with medial agranular cortex and orbital cortex; together, these three cortical areas may function as a network for directed attention in rats.

Afferent Pathways↗

Analysis of neural dynamics and memory organization.

We analysed neural network dynamics by a Caianiello type of equation with special reference to memory organization and the corresponding synaptic connection matrix. Global analysis of the dynamics yielded only stable equilibrium configurations and no periodic solutions.

Animals↗

[The neurobiology of developmental dyslexia: a survey].

One of the most common disorders affecting the ability to read is developmental dyslexia, which, unlike the alexia related to a loss of the capacity to read associated with brain damage, refers to a specific disorder in the acquisition of reading skills and becomes apparent in reiterated persistent difficulties in learning to read. A number of studies have attempted to detect structural and functional abnormalities that might be the origin of problems in learning to read. The use of functional neuroimaging techniques such as positron emission tomography (PET), spectroscopic magnetic resonance imaging (SMRI) and functional magnetic resonance imaging (fMRI) enables us to measure changes in the metabolic activity associated with alterations in the neuronal networks involved in the reading process. In this review, different studies are analysed in an attempt to identify alterations in the cortico subcortical regions which could be the origin of the developmental dyslexia. Results show that in dyslexics there is a temporoparietooccipital disconnection, and a disconnection with the left frontal cortex as regards the demands for fast auditory processing, as well as abnormalities in the connections between the temporoparietal cortex and the cerebellum with other regions of the brain. Such findings suggest that the altered areas of the brain do not only show a characteristic pattern of hypoactivation, but also that these alterations could be the cause of this malady. We highlight the importance of these findings in the diagnosis and rehabilitation of this population.

Dyslexia↗

A Bayesian approach to modeling dynamic effective connectivity with fMRI data.

A state-space modeling approach for examining dynamic relationship between multiple brain regions was proposed in Ho, Ombao and Shumway (Ho, M.R., Ombao, H., Shumway, R., 2005. A State-Space Approach to Modelling Brain Dynamics to Appear in Statistica Sinica). Their approach assumed that the quantity representing the influence of one neuronal system over another, or effective connectivity, is time-invariant. However, more and more empirical evidence suggests that the connectivity between brain areas may be dynamic which calls for temporal modeling of effective connectivity. A Bayesian approach is proposed to solve this problem in this paper. Our approach first decomposes the observed time series into measurement error and the BOLD (blood oxygenation level-dependent) signals. To capture the complexities of the dynamic processes in the brain, region-specific activations are subsequently modeled, as a linear function of the BOLD signals history at other brain regions. The coefficients in these linear functions represent effective connectivity between the regions under consideration. They are further assumed to follow a random walk process so to characterize the dynamic nature of brain connectivity. We also consider the temporal dependence that may be present in the measurement errors. ML-II method (Berger, J.O., 1985. Statistical Decision Theory and Bayesian Analysis (2nd ed.). Springer, New York) was employed to estimate the hyperparameters in the model and Bayes factor was used to compare among competing models. Statistical inference of the effective connectivity coefficients was based on their posterior distributions and the corresponding Bayesian credible regions (Carlin, B.P., Louis, T.A., 2000. Bayes and Empirical Bayes Methods for Data Analysis (2nd ed.). Chapman and Hall, Boca Raton). The proposed method was applied to a functional magnetic resonance imaging data set and results support the theory of attentional control network and demonstrate that this network is dynamic in nature.

Attention↗

Functional neural circuits for mental timekeeping.

Theories of mental timekeeping suggest frontostriatal networks may mediate performance of tasks requiring precise timing. We assessed whether frontostriatal networks are functionally integrated during the performance of timing tasks. Functional magnetic resonance imaging (fMRI) data from 31 healthy adults were collected during performance of several different types of discrete interval timing tasks. Independent component analysis (ICA) was used to examine functional connectivity within frontostriatal circuits. ICA identifies groups of spatially discrete brain regions sharing similar patterns of hemodynamic signal change over time. The results confirm the existence of a frontostriatal neural timing circuit that includes anterior cingulate gyrus, supplementary motor area, bilateral anterior insula, bilateral putamen/globus pallidus, bilateral thalamus, and right superior temporal gyrus and supramarginal gyrus. Several other distinct neural circuits were identified that may represent the neurobiological substrates of different information processing stages of mental timekeeping. Small areas of right cerebellum were engaged in several of these circuits, suggesting that cerebellar function may be important in, but not the primary substrate of, the mental timing tasks used in this experiment. These findings are discussed within the context of current biological and information processing models of neural timekeeping.

Acoustic Stimulation↗

Towards a cognitive neuroscience of consciousness: basic evidence and a workspace framework.

This introductory chapter attempts to clarify the philosophical, empirical, and theoretical bases on which a cognitive neuroscience approach to consciousness can be founded. We isolate three major empirical observations that any theory of consciousness should incorporate, namely (1) a considerable amount of processing is possible without consciousness, (2) attention is a prerequisite of consciousness, and (3) consciousness is required for some specific cognitive tasks, including those that require durable information maintenance, novel combinations of operations, or the spontaneous generation of intentional behavior. We then propose a theoretical framework that synthesizes those facts: the hypothesis of a global neuronal workspace. This framework postulates that, at any given time, many modular cerebral networks are active in parallel and process information in an unconscious manner. An information becomes conscious, however, if the neural population that represents it is mobilized by top-down attentional amplification into a brain-scale state of coherent activity that involves many neurons distributed throughout the brain. The long-distance connectivity of these 'workspace neurons' can, when they are active for a minimal duration, make the information available to a variety of processes including perceptual categorization, long-term memorization, evaluation, and intentional action. We postulate that this global availability of information through the workspace is what we subjectively experience as a conscious state. A complete theory of consciousness should explain why some cognitive and cerebral representations can be permanently or temporarily inaccessible to consciousness, what is the range of possible conscious contents, how they map onto specific cerebral circuits, and whether a generic neuronal mechanism underlies all of them. We confront the workspace model with those issues and identify novel experimental predictions. Neurophysiological, anatomical, and brain-imaging data strongly argue for a major role of prefrontal cortex, anterior cingulate, and the areas that connect to them, in creating the postulated brain-scale workspace.

Brain↗

Neurophysiological architecture of functional magnetic resonance images of human brain.

We investigated large-scale systems organization of the whole human brain using functional magnetic resonance imaging (fMRI) data acquired from healthy volunteers in a no-task or 'resting' state. Images were parcellated using a prior anatomical template, yielding regional mean time series for each of 90 regions (major cortical gyri and subcortical nuclei) in each subject. Significant pairwise functional connections, defined by the group mean inter-regional partial correlation matrix, were mostly either local and intrahemispheric or symmetrically interhemispheric. Low-frequency components in the time series subtended stronger inter-regional correlations than high-frequency components. Intrahemispheric connectivity was generally related to anatomical distance by an inverse square law; many symmetrical interhemispheric connections were stronger than predicted by the anatomical distance between bilaterally homologous regions. Strong interhemispheric connectivity was notably absent in data acquired from a single patient, minimally conscious following a brainstem lesion. Multivariate analysis by hierarchical clustering and multidimensional scaling consistently defined six major systems in healthy volunteers-- corresponding approximately to four neocortical lobes, medial temporal lobe and subcortical nuclei- - that could be further decomposed into anatomically and functionally plausible subsystems, e.g. dorsal and ventral divisions of occipital cortex. An undirected graph derived by thresholding the healthy group mean partial correlation matrix demonstrated local clustering or cliquishness of connectivity and short mean path length compatible with prior data on small world characteristics of non-human cortical anatomy. Functional MRI demonstrates a neurophysiological architecture of the normal human brain that is anatomically sensible, strongly symmetrical, disrupted by acute brain injury, subtended predominantly by low frequencies and consistent with a small world network topology.

Adult↗

Investigating the neural basis for functional and effective connectivity. Application to fMRI.

Viewing cognitive functions as mediated by networks has begun to play a central role in interpreting neuroscientific data, and studies evaluating interregional functional and effective connectivity have become staples of the neuroimaging literature. The neurobiological substrates of functional and effective connectivity are, however, uncertain. We have constructed neurobiologically realistic models for visual and auditory object processing with multiple interconnected brain regions that perform delayed match-to-sample (DMS) tasks. We used these models to investigate how neurobiological parameters affect the interregional functional connectivity between functional magnetic resonance imaging (fMRI) time-series. Variability is included in the models as subject-to-subject differences in the strengths of anatomical connections, scan-to-scan changes in the level of attention, and trial-to-trial interactions with non-specific neurons processing noise stimuli. We find that time-series correlations between integrated synaptic activities between the anterior temporal and the prefrontal cortex were larger during the DMS task than during a control task. These results were less clear when the integrated synaptic activity was haemodynamically convolved to generate simulated fMRI activity. As the strength of the model anatomical connectivity between temporal and frontal cortex was weakened, so too was the strength of the corresponding functional connectivity. These results provide a partial validation for using fMRI functional connectivity to assess brain interregional relations.

Auditory Perception↗

Sensations and brain processes.

A hypothesis on the physiological conditions of consciousness is presented. It is assumed that the occurrence of states of consciousness causally depends on the formation of complex representational structures. Cortical neural networks that exhibit a high representational activity develop higher-order, self-referential representations as a result of self-organizing processes. The occurrence of such states is identical with the appearance of states of consciousness. The underlying physiological processes can be identified. It is assumed that neural assemblies instantiate mental representations; hence consciousness depends on the rate at which large active assemblies are generated. The formation of assemblies involves the activation of the N-methyl-D-aspartate receptor channel complex which controls different forms of synaptic plasticity including rapid changes of the connection strengths. The various causes of unconsciousness (e.g., anaesthetics or brain stem lesions) have a common denominator: they directly or indirectly inhibit the formation of assemblies.

Animals↗

Brain dynamics during natural viewing conditions--a new guide for mapping connectivity in vivo.

We describe here a new way of obtaining maps of connectivity in the human brain based on interregional correlations of blood oxygen level-dependent (BOLD) signal during natural viewing conditions. We propose that anatomical connections are reflected in BOLD signal correlations during natural brain dynamics. This may provide a powerful approach to chart connectivity, more so than that based on the 'resting state' of the human brain, and it may complement diffusion tensor imaging. Our approach relies on natural brain dynamics and is therefore experimentally unbiased and independent of hypothesis-driven, specialized stimuli. It has the advantage that natural viewing leads to considerably stronger cortical activity than rest, thus facilitating detection of weaker connections. To validate our technique, we used functional magnetic resonance imaging (fMRI) to record BOLD signal while volunteers freely viewed a movie that was interrupted by resting periods. We used independent component analysis (ICA) to segregate cortical areas before characterizing the dynamics of their BOLD signal during free viewing and rest. Natural viewing and rest each revealed highly specific correlation maps, which reflected known anatomical connections. Examples are homologous regions in visual and auditory cortices in the two hemispheres and the language network consisting of Wernicke's area, Broca's area, and a premotor region. Correlations between regions known to be directly connected were always substantially higher than between nonconnected regions. Furthermore, compared to rest, natural viewing specifically increased correlations between anatomically connected regions while it decreased correlations between nonconnected regions. Our findings therefore demonstrate that natural viewing conditions lead to particularly specific interregional correlations and thus provide a powerful environment to reveal anatomical connectivity in vivo.

Acoustic Stimulation↗

The left intraparietal sulcus and verbal short-term memory: focus of attention or serial order?

One of the most consistently activated regions during verbal short-term memory (STM) tasks is the left intraparietal sulcus (IPS). However, its precise role remains a matter of debate. While some authors consider the IPS to be a specific store for serial order information, other data suggest that it serves a more general function of attentional focalization. In the current fMRI experiment, we investigated these two hypotheses by presenting different verbal STM conditions that probed recognition for word identity or word order and by assessing functional connectivity of the left IPS with distant brain areas. If the IPS has a role of attentional focalization, then it should be involved in both order and item conditions, but it should be connected to different brain regions, depending on the neural substrates involved in processing the different types of information (order versus phonological/orthographic) to be remembered in the item and order STM conditions. We observed that the left IPS was activated in both order and item STM conditions but for different reasons: during order STM, the left IPS was functionally connected to serial/temporal order processing areas in the right IPS, premotor and cerebellar cortices, while during item STM, the left IPS was connected to phonological and orthographic processing areas in the superior temporal and fusiform gyri. Our data support a position considering that the left IPS acts as an attentional modulator of distant neural networks which themselves are specialized in processing order or language representations. More generally, they strengthen attention-based accounts of verbal STM.

Adult↗

BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2.

Spontaneous neural activity is a basic property of the developing brain, which regulates key developmental processes, including migration, neural differentiation and formation and refinement of connections. The mechanisms regulating spontaneous activity are not known. By using transgenic embryos that overexpress BDNF under the control of the nestin promoter, we show here that BDNF controls the emergence and robustness of spontaneous activity in embryonic hippocampal slices. Further, BDNF dramatically increases spontaneous co-active network activity, which is believed to synchronize gene expression and synaptogenesis in vast numbers of neurons. In fact, BDNF raises the spontaneous activity of E18 hippocampal neurons to levels that are typical of postnatal slices. We also show that BDNF overexpression increases the number of synapses at much earlier stages (E18) than those reported previously. Most of these synapses were GABAergic, and GABAergic interneurons showed hypertrophy and a 3-fold increase in GAD expression. Interestingly, whereas BDNF does not alter the expression of GABA and glutamate ionotropic receptors, it does raise the expression of the recently cloned K(+)/Cl(-) KCC2 co-transporter, which is responsible for the conversion of GABA responses from depolarizing to inhibitory, through the control of the Cl(-) potential. Together, results indicate that both the presynaptic and postsynaptic machineries of GABAergic circuits may be essential targets of BDNF actions to control spontaneous activity. The data indicate that BDNF is a potent regulator of spontaneous activity and co-active networks, which is a new level of regulation of neurotrophins. Given that BDNF itself is regulated by neuronal activity, we suggest that BDNF acts as a homeostatic factor controlling the emergence, complexity and networking properties of spontaneous networks.

Animals↗

A hierarchical neuronal network for planning behavior.

Planning a goal-directed sequence of behavior is a higher function of the human brain that relies on the integrity of prefrontal cortical areas. In the Tower of London test, a puzzle in which beads sliding on pegs must be moved to match a designated goal configuration, patients with lesioned prefrontal cortex show deficits in planning a goal-directed sequence of moves. We propose a neuronal network model of sequence planning that passes this test and, when lesioned, fails in a way that mimics prefrontal patients' behavior. Our model comprises a descending planning system with hierarchically organized plan, operation, and gesture levels, and an ascending evaluative system that analyzes the problem and computes internal reward signals that index the correct/erroneous status of the plan. Multiple parallel pathways connecting the evaluative and planning systems amend the plan and adapt it to the current problem. The model illustrates how specialized hierarchically organized neuronal assemblies may collectively emulate central executive or supervisory functions of the human brain.

Behavior↗