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Global relationship between anatomical connectivity and activity propagation in the cerebral cortex.

Anatomical connectivity is a prerequisite for cooperative interactions between cortical areas, but it has yet to be demonstrated that association fibre networks determine the macroscopical flow of activity in the cerebral cortex. To test this notion, we constructed a large-scale model of cortical areas whose interconnections were based on published anatomical data from tracing studies. Using this model we simulated the propagation of activity in response to activation of individual cortical areas and compared the resulting topographic activation patterns to electrophysiological observations on the global spread of epileptic activity following intracortical stimulation. Here we show that a neural network with connectivity derived from experimental data reproduces cortical propagation of activity significantly better than networks with different types of neighbourhood-based connectivity or random connections. Our results indicate that association fibres and their relative connection strengths are useful predictors of global topographic activation patterns in the cerebral cortex. This global structure-function relationship may open a door to explicit interpretation of cortical activation data in terms of underlying anatomical connectivity.

Animals↗

Altered neural electrophysiological properties in the anterior cingulate cortex in a mouse model of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental genetic disease associated with multiple metabolic and behavioural abnormalities converging into a distinctive clinical phenotype characterized by insatiable appetite leading to hyperphagia and eventual morbid obesity. The PWS spectrum results from deficiencies in paternally imprinted chromosome 15q11-13 region clustering around non-coding RNA multiple-repeat gene Snord116. A PWS mouse model with paternal Snord116 deletion (Snord116del) revealed multiple expected behavioural traits but failed to reproduce obesity in experimental paradigms designed to uncover homeostatic hypothalamic mechanisms of hyperphagia, while the possibility for pathologic hedonic overdrive underlying hyperphagic behaviours was not studied. In Snord116del mice, we examined functional properties of pyramidal neurons (PyNs) in the anterior cingulate cortex (ACC), the brain area commonly associated with goal-oriented and choice-outcome processing, including the value assessment of food items. We found indications of higher dendritic complexity and stronger afferent excitatory connectivity compared to controls. A strong excitatory input into Snord116del PyNs was balanced by a more hyperpolarized resting membrane potential, rendering lower soma excitability, improved signal-to-noise discrimination and stronger low-pass filtering. The enhanced excitatory network-tuning ability originating from Snord116 deficiency may explain the previously reported better performance of Snord116del over wild-type mice in working-for-food behavioural tests, whereas in humans it might entail exaggerated reward-seeking behaviour since early childhood when food is the main attractant. Our analysis of previously published genomic databases revealed candidate genes responsible for the abnormal functional neuronal phenotype caused by Snord116 deletion, including K+ and Na+ voltage-dependent ion channels, protein kinases, phosphatases and components of the mechanistic target of rapamycin (mTOR) intracellular signalling pathway. KEY POINTS: Altered biophysical characteristics and parameters of neuronal connectivity in pyramidal neurons in the anterior cingulate cortex (ACC) in Snord116 deletion mice. Alterations include augmented afferent synaptic input, altered resting state and firing properties of ACC pyramidal neurons. Our findings uncover a possible mechanistic basis for altered ACC functionality in Prader-Willi syndrome.

Animals↗

Functional anatomy of the therapeutic effects of prism adaptation on left neglect.

OBJECTIVE: To investigate the anatomic substrates underlying the beneficial effect of prism adaptation in five patients with persistent left neglect following right stroke. METHODS: In a functional imaging PET study, we used a covariation analysis to examine linear changes of regional cerebral blood flow over sessions as a function of left neglect improvement. RESULTS: The network of significant brain regions associated with improvement of left neglect performance produced by prism adaptation involved the right cerebellum, the left thalamus, the left temporo-occipital cortex, the left medial temporal cortex, and the right posterior parietal cortex. CONCLUSION: Our results suggest that the realignment of visuomotor coordinates is processed by the cerebellum and that low level sensorimotor adaptation actively modulates cerebral areas, albeit now relying on intact cerebellocerebral connections. Hence, our data support the hypothesis that the beneficial effect of prism adaptation on the clinical presentation of left neglect derives from modulation of cortical regions implicated in spatial cognition.

Adaptation, Physiological↗

Neural lineages of the Drosophila brain: a three-dimensional digital atlas of the pattern of lineage location and projection at the late larval stage.

The late larval brain consists of embryonically produced primary neurons forming a deep core cortex, surrounded at the surface by approximately 100 secondary lineages. Each secondary lineage forms a tract (secondary lineage tract) with an invariant and characteristic trajectory. Within the neuropile, tracts of neighboring lineages bundle together to form secondary tract systems. In this paper, we visualized secondary lineages by the global marker BP106 (neurotactin), as well as green fluorescent protein-labeled clones and thereby establish a comprehensive digital atlas of secondary lineages. The information contained in this atlas is the location of the lineage within the cortex, the neuropile compartment contacted by the lineage tract, and the projection pattern of the lineage tract within the neuropile. We have digitally mapped the expression pattern of three genes, sine oculis, period, and engrailed into the lineage atlas. The atlas will enable us and others to analyze the phenotype of mutant clones in the larval brain. Mutant clones can only be interpreted if the corresponding wild-type clone is well characterized, and our lineage atlas, which visualizes all wild-type lineages, will provide this information. Secondly, secondary lineage tracts form a scaffold of connections in the neuropile that foreshadows adult nerve connections. Thus, starting from the larval atlas and proceeding forward through pupal development, one will be able to reconstruct adult brain connectivity at a high level of resolution. Third, the atlas can serve as a repository for genes expressed in lineage-specific patterns.

Anatomy, Artistic↗

[The robotization of neurosurgery: state of the art and future outlook].

Neurosurgery is by excellence a field of application for robots, based on multimodal image guidance. Specific motorized tools have been already developed and routinely applied in stereotaxy to position a probe holder or in conventional neurosurgery to hold a microscope oriented towards a given target. The potentialities of these approaches have triggered industrial developments currently commercially available. These systems use data bases, primarily coming from multimodal numerical images from X-ray radiology to magnetic resonance imaging. These spatially encoded data are transferred through digital networks to workstations where images can be processed and surgical procedures are preplanned, then transferred to the robotic systems to which they are connected. We have been using a stereotactic robot since 1989 and a microscope robot since 1995 in various surgical routine procedures. The future of these applications mainly rely on the technical progress in informatics, about image recognition to adapt the preplanning to the actual surgical situation, to correct brain shifts for instance, about image fusion, integrated knowledge such such as brain atlases, as well as virtual reality. The future developments, covering surgical procedure, research and teaching, will sure be far beyond our wildest expectations.

Forecasting↗

Distribution of serotonin in the central nervous system of the blood-feeding heteropteran, Triatoma infestans (Heteroptera: Reduviidae).

The distribution of serotonin was studied in the Triatoma infestans central nervous system by using immunocytochemistry. Serotonin immunoreactive cell bodies and fibers were observed in the brain, subesophageal ganglion, and thoracic ganglia. In the brain, serotonin-like immunoreactivity was detected in a limited number of somata, which gave rise to an extensive network of labeled neurites in patterned as well as in nonglomerular neuropils. Immunolabeled perikarya were observed in the optic lobe and in the anteromedial and caudolateral soma rinds of the protocerebrum. Deutocerebral immunoreactive somata were mainly found in the medial layer surrounding the antennal lobe glomeruli, as well as in relationship to the antennal mechanosensory and motor center. The subesophageal ganglion contained serotonin immunoreactive perikarya of variable sizes and moderate to low density of positive fibers. In the prothoracic ganglion, immunoreactive somata were detected near the cephalic connectives as well as in its caudal end. Serotonin immunoreactive somata and fibers were observed in the posterior ganglion of the thorax, with the abdominal neuromeres harboring the highest number of immunolabeled perikarya. These results show that there is a widespread unique serotonergic system in the CNS of Triatoma infestans and suggest that the indolamine could act as a neuromodulator or as a neurohormone.

Animals↗

Functional disconnectivity in subjects at high genetic risk of schizophrenia.

Schizophrenia is a highly heritable psychotic disorder. It has been suggested that deficits of the established state arise from abnormal interactions between brain regions. We sought to examine whether such connectivity abnormalities would be present in subjects at high genetic risk for the disorder. Functional connectivity analysis was carried out on functional MRI images from 21 controls and 69 high risk subjects performing the Hayling sentence completion task; 27 high risk subjects reported isolated psychotic symptoms, the remaining high risk subjects and controls did not. There were no significant differences in task performance between the groups. Based on previous findings we hypothesized: (i) state-related differences in connectivity between dorsolateral prefrontal cortex and lateral temporal lobe; (ii) genetically mediated reductions in a medial prefrontal-thalamic-cerebellar network; and (iii) increased prefrontal-parietal connectivity in high risk subjects (to a greater extent in those with isolated psychotic symptoms). Connectivity analysis was performed in two ways: with and without variance associated with task effects modelled and removed from the data. We did not find evidence to support our first hypothesis with either analysis method. However, consistent with hypothesis (ii), decreased connectivity between right medial prefrontal regions and contralateral cerebellum was found. This was only statistically significant in the analysis with task effects modelled and removed from the data. Finally, consistent with hypothesis (iii), increased connectivity between the left parietal and left prefrontal regions in high risk subjects was found in both analyses. These results, all in a situation uncontaminated by the effects of anti-psychotic medication, performance differences and prolonged illness, suggest there are abnormalities in functional connectivity over and above those attributable to task effects in high risk subjects. These connectivity abnormalities may underlie the diverse deficits seen in the established condition and the more subtle deficits seen in close relatives of those with the disorder.

Adolescent↗

Rhythmic activity from transverse brainstem slice of neonatal rat is modulated by nitric oxide.

We investigated the role of nitric oxide (NO) in the modulation of respiratory-like activity recorded from hypoglossal rootlets in brainstem slices of neonatal rats (P0-P8). Sodium nitroprusside (SNP), S-Nitroso-N-acetyl-D,L-penicillamine (SNAP) and diethylamine-NO (DEA-NO), three NO-donors, reversibly increased hypoglossal burst amplitude with inconsistent effects on burst frequency. Similar effects were also obtained with the endogenous substrate of nitric oxide synthase (NOS), L-arginine, whereas the inactive enantiomer D-arginine had no effect. The NO-trap agent methylene blue significantly depressed both the amplitude and frequency of hypoglossal activity while hemoglobin depressed only the amplitude. Furthermore, the addition of NO-trap agents significantly attenuated the excitatory response to SNP. Inhibiting NOS with either N(omega)-Nitro-L-Arginine (L-NNA) or 7-Nitroindazole (7-NI), decreased the amplitude of hypoglossal activity with no effects on frequency. Histochemical analysis of NADPH-diaphorase activity, a marker for NOS, was performed on slices not treated pharmacologically and in brainstem sections of newborn rats, perfused in situ. Comparison between in vitro and in vivo conditions indicated that NOS activity was maintained in slice preparations. Neurons in the ambiguus and hypoglossal nuclei (dorsal division) exhibited a granular staining, suggesting the presence of NADPHd-positive terminals. Neurons with cytoplasmic staining were identified in regions connected to the hypoglossal nucleus (nucleus tractus solitarius, paramedian and gigantocellular reticular nuclei). These neurons might be involved in nitrergic control of hypoglossal activity. Both pharmacological and histochemical data suggest that endogenous NO may reinforce the output activity of the medullary respiratory network.

Action Potentials↗

Attention-dependent changes of activation and connectivity in dichotic listening.

Functional studies of auditory spatial attention generally report enhanced neural responses in auditory cortical regions. However, activity in regions of the spatial attentional network as described in the visual modality is not consistently observed. Data analysis limitations due to oppositely lateralized activity depending on the side of attentional orientation and heterogeneity of paradigms makes it hard to untangle the possible causes of these various activation patterns. In the present article we present a PET study of auditory spatial attention in which we manipulated orientation of attention, attentional load, and difficulty of the task by means of the dichotic listening paradigm. Moreover, we designed a systematic, voxel-specific, method in order to deal with oppositely lateralized activity. The results show that when listeners are involved in auditory spatial attention tasks an interacting network of frontal, temporal, and parietal regions is activated. Selective orientation toward one side mostly yields activity and connectivity modulations in the hemisphere contralateral to the attended side while in divided attention activity is mostly bilateral. Taken together, our observations are consistent with the idea of a multimodal large-scale attentional network.

Adult↗

The human cerebro-cerebellar system: its computing, cognitive, and language skills.

In this review of the human cerebro-cerebellar system, the focus is on the possible contributions of the cerebellum to cognitive and language functions. The role of the cerebellum in these human functions has tended to be obscured by the traditional preoccupation with the motor functions of the cerebellum, which have been widely observed in other vertebrates as well. In the human brain, some phylogenetically new parts evolved and enlarged in the cerebellum, concomitantly with the enlargement of association areas in the cerebral cortex. Anatomical evidence and behavioral evidence combine to suggest that this enlarged cerebellum contributes not only to motor function but also to some sensory, cognitive, linguistic, and emotional aspects of behavior. The anatomical evidence derives from the modularity of the cerebellum, whose cortical nerve cells are organized into longitudinal micro-modules, which are arrayed perpendicular to the cortical surface and parallel to each other. The number of these micro-modules increased when the cerebellum enlarged, which enlarged the computing capabilities of the network. (From principles underlying the processing of information, it is known that when modules with modest processing capabilities are assembled in large numbers in parallel, the resulting network can achieve remarkably powerful computing capabilities.) Such cerebellar computing capabilities can be utilized in the different areas of the cerebral cortex to which the cerebellum sends signals. The cerebellar output connections convey signals through the thalamus to the cerebral cortex in segregated channels of communication, which preserve the modularity of the cerebellum. Through these channels, modules in the lateral cerebellum can send signals to new cognitive and language areas of the cerebral cortex, such as Broca's area in the prefrontal cortex. The anatomy of the human cerebro-cerebellar system therefore suggests that the cerebellum can contribute to the learning not only of motor skills but also of some cognitive and language skills. Supporting this anatomical evidence is the mounting behavioral evidence, obtained both in normal brains and in clinical studies, which indicates that the lateral cerebellum is indeed involved in some cognitive and language functions.

Brain↗

Assessing the working memory network: studies with functional magnetic resonance imaging and structural equation modeling.

A considerable body of evidence supports the notion that the neurofunctional substrate of working memory is not only related to the integrity of the prefrontal cortex, but also to the concerted interplay of widespread interacting networks including the parietal cortex, subcortical regions and cerebellar areas. Modern functional brain imaging techniques such as functional magnetic resonance imaging (fMRI) have provided a detailed picture of functional neuroanatomy subserving working memory functions. Most of the earlier functional studies were directed toward the identification of brain areas subserving specific cognitive domains in terms of a functional segregation. More recently, different multivariate techniques were employed to specifically address measures of functional or effective connectivity. Structural equation modeling (SEM) or path analysis is one of the most often used methods to model interactions among covarying brain areas in an explicitly model-based approach. The present review will focus on basic methodological issues of SEM for the analysis of fMRI datasets in studies of working memory. Aside from a discussion of previous studies and their essential findings, advanced methodological issues and caveats as well as future perspectives of the method will be addressed.

Brain↗

Neural timing nets.

Formulations of artificial neural networks are directly related to assumptions about neural coding in the brain. Traditional connectionist networks assume channel-based rate coding, while time-delay networks convert temporally-coded inputs into rate-coded outputs. Neural timing nets that operate on time structured input spike trains to produce meaningful time-structured outputs are proposed. Basic computational properties of simple feedforward and recurrent timing nets are outlined and applied to auditory computations. Feed-forward timing nets consist of arrays of coincidence detectors connected via tapped delay lines. These temporal sieves extract common spike patterns in their inputs that can subserve extraction of common fundamental frequencies (periodicity pitch) and common spectrum (timbre). Feedforward timing nets can also be used to separate time-shifted patterns, fusing patterns with similar internal temporal structure and spatially segregating different ones. Simple recurrent timing nets consisting of arrays of delay loops amplify and separate recurring time patterns. Single- and multichannel recurrent timing nets are presented that demonstrate the separation of concurrent, double vowels. Timing nets constitute a new and general neural network strategy for performing temporal computations on neural spike trains: extraction of common periodicities, detection of recurring temporal patterns, and formation and separation of invariant spike patterns that subserve auditory objects.

Action Potentials↗

Continuum model of mnemonic and amnesic phenomena.

Amnesia in its various forms is characterized by defects in one or more components of a complex system. Implantation of short-term memory occurs in the hippocampus, while long-term memory is essentially located in the neocortex; these regions are interconnected through complex synaptic structures. In the hippocampus, physiological data show that, as predicted by Hebb, excitatory synapses between nearby excitatory cells become strengthened by simultaneous activation. In contrast with this local process, the preponderance of clinical and experimental evidence indicates that cortical recall of a "memory" is the reconstruction of fragments stored in different synaptically distant brain regions. A mathematical model of memory must reconcile this apparent contradiction as well as explain how many different memories and "ideas" can be assembled within a given anatomical area. Continuum theory, which treats an ensemble of "cell assemblies" or neural networks, offers a step in this direction. Linear analysis using this approach shows that it is the nature of the neural continuum to generate activity waves of wavelength greater than synaptic connection ranges. These waves grow under certain circumstances, and their wavelength is controlled by the synaptic parameters. Both hippocampal and cortical tissue are subject to such wave growth. In the hippocampus, the local Hebbian strengthening controls the global wave growth, making the difference between wave decay and growth. The cortical wave structure can become very complex, so that reproducible memory recall as well as "creative thought" can be accommodated in the theory. Deficits in the functioning of the system may also be evaluated potentially by means of "goodness-of-fit" of the clinical and spatially resolved data with the model.

Algorithms↗

Long-range EEG phase synchronization during an arithmetic task indexes a coherent cortical network simultaneously measured by fMRI.

An open question lies in whether or not distributed activities in the distant brain regions are integrated into a coherent ensemble for cognitive information processing. Long-range phase synchronization is often observed by scalp EEG measurements during cognitive tasks and is considered to provide a possible neural principle for the functional integration of distributed neural activities. Synchronization could be reflected at the neuron firing level or at the local field potential and could appear in the scalp EEG under certain conditions on neural spatial and temporal coherence. To examine if phase synchronization is concerned with the integration of distant regions, we proposed a method to extract brain activities associated with task-dependent phase synchronization by combining simultaneous fMRI and EEG. By applying this method in a mental arithmetic task, we found a dominant task-dependent increase of phase synchronization around 14 Hz (in beta frequency) across bilateral parietal sites that were associated with both negative and positive BOLD responses. Functional connectivity analyses of these regions demonstrated that an increase in hemispheric beta synchronization was associated with a linking between the cross-hemispheric regions (left angular gyrus and right superior parietal gyrus) and also among the anterior-posterior regions (right dorsolateral prefrontal cortex, putamen, and right superior temporal gyrus). These findings indicate that the positive BOLD regions (dorsolateral prefrontal cortex and superior parietal lobule) are linked with other negative BOLD regions. We also discussed the possible importance of beta synchronization in the formation of a working memory network.

Adult↗

On the matter of rules. Past-tense formation and its significance for cognitive neuroscience.

If neuronal models are successful, they will account for specifically human complex behaviours. Most of these behaviours can be described as governed by rules. In recent years, much effort has been spent to elucidate the neuronal basis of rules, and many researchers have focussed on modelling rules and regularities underlying language, particularly those relevant for past-tense formation. After introducing problems posed by past-tense formation, important aspects of recent controversies between connectionists and linguists concerning the nature of rules will be reviewed and analysed on the basis of elementary simulations. It is argued that modular networks with varying connection probabilities between their layers would be ideal for modelling learning and processing of past-tense formation. The motivation for postulating such networks comes from neurobiological models of language and from neuroanatomical data about cortico-cortical connectivity. Furthermore, such modular networks may explain double dissociations of regular and irregular past-tense formation in neurological patients, as reported in recent neuropsychological publications. It is concluded that past-tense formation does not pose problems to pattern associators, given that some structure is built into the network which approximates wirings in the human cortex.

Brain↗

Storage capacity diverges with synaptic efficiency in an associative memory model with synaptic delay and pruning.

It is known that storage capacity per synapse increases by synaptic pruning in the case of a correlation-type associative memory model. However, the storage capacity of the entire network then decreases. To overcome this difficulty, we propose decreasing the connectivity while keeping the total number of synapses constant by introducing delayed synapses. In this paper, a discrete synchronous-type model with both delayed synapses and their prunings is discussed as a concrete example of the proposal. First, we explain the Yanai-Kim theory by employing statistical neurodynamics. This theory involves macrodynamical equations for the dynamics of a network with serial delay elements. Next, considering the translational symmetry of the explained equations, we rederive macroscopic steady-state equations of the model by using the discrete Fourier transformation. The storage capacities are analyzed quantitatively. Furthermore, two types of synaptic prunings are treated analytically: random pruning and systematic pruning. As a result, it becomes clear that in both prunings, the storage capacity increases as the length of delay increases and the connectivity of the synapses decreases when the total number of synapses is constant. Moreover, an interesting fact becomes clear: the storage capacity asymptotically approaches 2/pi due to random pruning. In contrast, the storage capacity diverges in proportion to the logarithm of the length of delay by systematic pruning and the proportion constant is 4/pi. These results theoretically support the significance of pruning following an overgrowth of synapses in the brain and may suggest that the brain prefers to store dynamic attractors such as sequences and limit cycles rather than equilibrium states.

Action Potentials↗

Patching the glia reveals the functional organisation of the brain.

The neuroglia was initially conceived by Rudolf Virchow as a non-cellular connective tissue holding neurones together. In 1894, Carl Ludwig Schleich proposed a hypothesis of fully integrated and interconnected neuronal-glial circuits as a substrate for brain function. This hypothesis received direct experimental support only hundred years later, after several physiological techniques, and most notably the patch-clamp method, were applied to glial cells. These experiments have demonstrated the existence of active and bi-directional neuronal-glial communications, integrating neuronal networks and glial syncytium into one functional circuit. The data accumulated during last 15 years prompt rethinking of the neuronal doctrine towards more inclusive concept, which regards both neurones and glia as equally responsible for information processing in the brain.

Animals↗

Frequency specific changes in regional cerebral blood flow and motor system connectivity following rTMS to the primary motor cortex.

Repetitive transcranial magnetic stimulation (rTMS) to the human primary motor cortex (M1) causes bidirectional changes in corticospinal excitability depending on the stimulation frequency used. We used functional brain imaging to compare the effects of 5 Hz and 1 Hz-rTMS on local and inter-regional connectivity within the motor system. Regional cerebral blood flow (rCBF) was measured as a marker of synaptic activity at rest and during freely selected finger movements. We hypothesized that increased cortical excitability induced by 5 Hz-rTMS over M1 has an opposite effect on the synaptic activity and the connectivity of the motor network from the decreased cortical excitability induced by 1 Hz-rTMS. rTMS at both frequencies induced similar changes in rCBF at the site of stimulation and within areas of the motor network engaged by the task. The two frequencies showed different effects on movement-related coupling between motor areas. Connectivity analyses also indicated a differential effect of 5 and 1 Hz-rTMS on motor network connectivity, suggesting a role for an inferomedial portion of left M1 and left dorsal premotor cortex in maintaining performance. These results suggest that rapid reorganization of the motor system occurs to maintain task performance during periods of altered cortical excitability. This reorganization differs according to the modulation of excitability which is a function of rTMS frequency. This study extends the work of Lee et al. (Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V. Rothwell, J.C. Frackowiak, R.S. Friston, K.J., 2003. Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J. Neurosci. 23, 5308-5318.) by providing evidence that the pattern of acute reorganization in the motor network following rTMS depends on the direction of conditioning.

Adult↗