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Correlations in low-frequency BOLD fluctuations reflect cortico-cortical connections.

Cross-correlation of low-frequency temporal fluctuations (<0.08 Hz) was used to correlate widely separated anatomic regions during continuous performance of a spatial working memory task. The regions of highest correlation to right-hemisphere dorsolateral prefrontal cortex correspond to the regions of largest baseline signal change in a conventional block-style functional MRI paradigm. Additionally, it is shown that the correlations between elements of the functional network increase during performance of a task that activates the network when compared to a task that does not directly stimulate the functionally connected network.

Attention↗

An intimate connection: Oliver Zangwill and the emergence of neuropsychology in Britain.

In this article, the author argues that a number of conditions conspired to place the Cambridge psychologist Oliver Zangwill in a pivotal position for pursuing and promoting neuropsychology in Britain after World War II. In broad terms, these were the background and experience of Zangwill himself, the practical engagement of psychologists with patients with brain damage, neurologists, and psychiatrists, the introduction of medical reform including the establishment of a National Health Service, rekindled interest in cortical localization, and the elite social networks that existed in medicine and university life in postwar Britain. The author claims that the career of Zangwill reveals rather than obscures the importance of these wider conditions and demonstrates an unusually close connection between an individual and the emergence of a subdiscipline.

Brain Injuries↗

Brain connectivity related to working memory performance.

Several brain areas show signal decreases during many different cognitive tasks in functional imaging studies, including the posterior cingulate cortex (PCC) and a medial frontal region incorporating portions of the medial frontal gyrus and ventral anterior cingulate cortex (MFG/vACC). It has been suggested that these areas are components in a default mode network that is engaged during rest and disengaged during cognitive tasks. This study investigated the functional connectivity between the PCC and MFG/vACC during a working memory task and at rest by examining temporal correlations in magnetic resonance signal levels between the regions. The two regions were functionally connected in both conditions. In addition, performance on the working memory task was positively correlated with the strength of this functional connection not only during the working memory task, but also at rest. Thus, it appears these regions are components of a network that may facilitate or monitor cognitive performance, rather than becoming disengaged during cognitive tasks. In addition, these data raise the possibility that the individual differences in coupling strength between these two regions at rest predict differences in cognitive abilities important for this working memory task.

Adult↗

Dynamics and bifurcations of two coupled neural oscillators with different connection types.

In this paper we present an oscillatory neural network composed of two coupled neural oscillators of the Wilson-Cowan type. Each of the oscillators describes the dynamics of average activities of excitatory and inhibitory populations of neurons. The network serves as a model for several possible network architectures. We study how the type and the strength of the connections between the oscillators affect the dynamics of the neural network. We investigate, separately from each other, four possible connection types (excitatory-->excitatory, excitatory-->inhibitory, inhibitory-->excitatory, and inhibitory-->inhibitory) and compute the corresponding bifurcation diagrams. In case of weak connections (small strength), the connection of populations of different types lead to periodic in-phase oscillations, while the connection of populations of the same type lead to periodic anti-phase oscillations. For intermediate connection strengths, the networks can enter quasiperiodic or chaotic regimes, and can also exhibit multistability. More generally, our analysis highlights the great diversity of the response of neural networks to a change of the connection strength, for different connection architectures. In the discussion, we address in particular the problem of information coding in the brain using quasiperiodic and chaotic oscillations. In modeling low levels of information processing, we propose that feature binding should be sought as a temporally coherent phase-locking of neural activity. This phase-locking is provided by one or more interacting convergent zones and does not require a central ¿top level¿ subcortical circuit (e.g., the septo-hippocampal system). We build a two layer model to show that although the application of a complex stimulus usually leads to different convergent zones with high frequency oscillations, it is nevertheless possible to synchronize these oscillations at a lower frequency level using envelope oscillations. This is interpreted as a feature binding of a complex stimulus.

Animals↗

Intercellular communication in the brain: wiring versus volume transmission.

During the past two decades several revisions of the concepts underlying interneuronal communication in the central nervous system have been advanced. We propose here to classify communicational phenomena between cells of the central neural tissue under two general frames: "wiring" and "volume" transmission. "Wiring" transmission is defined as intercellular communication occurring through a well-defined connecting structure. Thus, wiring transmission is characterized by the presence of physically identifiable communication channels within the neuronal and/or glial cell network. It includes synaptic transmission but also other types of intercellular communication through a connecting structure (e.g., gap junctions). "Volume" transmission is characterized by signal diffusion in a three-dimensional fashion within the brain extracellular fluid. Thus, multiple, structurally often not well characterized extracellular pathways connect intercommunicating cells. Volume transmission includes short- (but larger than synaptic cleft, i.e. about 20 nm) and long-distance diffusion of signals through the extracellular and cerebrospinal fluid. It must be underlined that the definitions of wiring and volume transmission focus on the modality of transmission and are neutral with respect to the source and target of the transmission, as well as type of informational substance transmitted. Therefore, any cell present in the neural tissue (neurons, astroglia, microglia, ependyma, tanycytes, etc.) can be a source or a target of wiring and volume transmission. In this paper we discuss the basic definitions and some distinctive characteristics of the two types of transmission. In addition, we review the evidence for different types of intercellular communication besides synaptic transmission in the central nervous system during phylogeny, and in vertebrates in physiological and pathological conditions.

Animals↗

Impaired thalamocortical connectivity in humans during general-anesthetic-induced unconsciousness.

Whereas converging lines of evidence suggest that anesthetic-induced unconsciousness may result from disruption of functional interactions within neural networks involving the thalamus and cerebral cortex, the effects anesthetics have on human thalamocortical connectivity remain unexamined with current neuroimaging techniques. To address this issue we retrospectively analyzed positron emission tomography data from 11 volunteers scanned for regional cerebral glucose utilization (rCMRglu) when awake and again during isoflurane- (n = 6) or halothane- (n = 5) induced unconsciousness using statistical parametric mapping (SPM99) and structural equation modeling. A main effect analysis, contrasting awake and unconscious metabolic activity, localized a discrete region of the left va/vl thalamus whose relative rCMRglu activity was significantly suppressed (P < 0.05, corrected) during the unconscious state. To identify brain regions whose functional connectivity with this region of the thalamus was impaired during the unconscious state, a psychophysiological interaction analysis was performed. This analysis revealed effects predominantly in topographically related areas of the primary motor and supplementary motor association cortices. Structural equation modeling of a neuroanatomical network encompassing these empirically identified regions revealed significant state-related changes in effective connectivity (chi(2)diff (6)-15.88; P < 0.05) which primarily involved impairment of thalamocortical and corticocortical projections during the unconscious state. These findings support the hypothesis that a mechanistic component underlying general-anesthetic-induced unconsciousness involves disruption of functional interactions within thalamocortical neural networks.

Anesthesia, General↗

The supramammillary area: its organization, functions and relationship to the hippocampus.

The supramammillary area of the hypothalamus, although small in size, can have profound modulatory effects on the hippocampal formation and related temporal cortex. It can control hippocampal plasticity and also has recently been shown to contain cells that determine the frequency of hippocampal rhythmical slow activity (theta rhythm). We review here its organization and anatomical connections providing an atlas and a new nomenclature. We then review its functions particularly in relation to its links with the hippocampus. Much of its control of behaviour and its differential activation by specific classes of stimuli is consistent with a tight relationship with the hippocampus. However, its ascending connections involve not only caudal areas of the cortex with close links to the hippocampus but also reciprocal connections with more rostral areas such as the infralimbic and anterior cingulate cortices. These latter areas appear to be the most rostral part of a network that, via the medial septum, hippocampus and lateral septum, is topographically mapped into the hypothalamus. The supramammillary area is thus diffusely connected with areas that control emotion and cognition and receives more topographically specific return information from areas that control cognition while also receiving ascending information from brain stem areas involved in emotion. We suggest that it is a key part of a network that recursively transforms information to achieve integration of cognitive and emotional aspects of goal-directed behaviour.

Animals↗

Bistable network behavior of layer I interneurons in auditory cortex.

GABAergic interneurons in many areas of the neocortex are mutually connected via chemical and electrical synapses. Previous computational studies have explored how these coupling parameters influence the firing patterns of interneuronal networks. These models have predicted that the stable states of such interneuronal networks will be either synchrony (near zero phase lag) or antisynchrony (phase lag near one-half of the interspike interval), depending on network connectivity and firing rates. In certain parameter regimens, the network can be bistable, settling into either stable state depending on the initial conditions. Here, we investigated how connectivity parameters influence spike patterns in paired recordings from layer I interneurons in brain slices from juvenile mice. Observed properties of chemical and electrical synapses were used to simulate connections between uncoupled cells via dynamic clamp. In uncoupled pairs, action potentials induced by constant depolarizing currents had randomly distributed phase differences between the two cells. When coupled with simulated chemical (inhibitory) synapses, however, these pairs exhibited a bimodal firing pattern, tending to fire either in synchrony or in antisynchrony. Combining electrical with chemical synapses, prolonging tau(Decay) of inhibitory connections, or increasing the firing rate of the network all resulted in enhanced stability of the synchronous state. Thus, electrical and inhibitory synaptic coupling constrain the relative timing of spikes in a two-cell network to, at most, two stable states, the stability and precision of which depend on the exact parameters of coupling.

Animals↗

Changes in brain functional connectivity in Alzheimer-type and multi-infarct dementia.

Clinical and neuropathological evaluation of elderly subjects with dementia has traditionally concentrated upon the focal distribution of brain disease, ignoring changes in the complex connections that link brain areas and that are crucial for cognition. We examined subjects with the two most common forms of dementia in the elderly (dementia of the Alzheimer type or DAT, and multi-infarct dementia or MID); and used electroencephalographic (EEG) coherence to examine the effects of these illnesses on the functional connections between brain areas. We studied coherence between brain areas known to be linked by two different types of connections: (i) dense narrow bands of long corticocortical fibres; (ii) broad complex networks of corticocortical and corticosubcortical fibres. Areas that were linked by dense narrow bands of long corticocortical fibres showed greatly diminished coherence in subjects with DAT; among MID subjects, this coherence was not significantly affected. Areas that were linked by broad connective networks showed the largest decreases in coherence among MID subjects. These findings are consistent with neuropathological evidence that Alzheimer's disease is a neocortical 'disconnection syndrome' in which there is a loss of structural and functional integrity of long corticocortical tracts. The findings further suggest that the vascular disease of MID most prominently affects broad fibre networks that may be more vulnerable to diffuse subcortical vascular damage. A ratio of coherence from complex corticocortical-corticosubcortical networks divided by coherence from long corticocortical tracts correctly classified 76% of subjects into DAT and MID categories. Overall, these results indicate that EEG coherence detects basic pathophysiological differences between subjects with DAT and MID, and that these differences may be clinically useful.

Aged↗

Physical realizability of small-world networks.

Supplementing a lattice with long-range connections effectively models small-world networks characterized by a high local and global interconnectedness observed in systems ranging from society to the brain. If the links have a wiring cost associated with their length l, the corresponding distribution q(l) plays a crucial role. Uniform length distributions have received the most attention despite indications that q(l) approximately l(-alpha) exists-e.g., for integrated circuits, the Internet, and cortical networks. While length distributions of this type were previously examined in the context of navigability, we here discuss for such systems the emergence and physical realizability of small-world topology. Our simple argument allows us to understand under which condition and at what expense a small world results.

Journal Article↗

Developmental aspects of the basal ganglia and therapeutic perspectives.

Development and sex hormones play an important role in the expression of seizures. Sex-specific differences in the development of seizure suppressing neuronal networks may account, at least in part, for age- and sex related susceptibility to seizures. The substantia nigra pars reticulata is a site involved in the control of seizures. In adult male rats, there are two distinct GABAA sensitive regions within the substantia nigra pars reticulata, which mediate opposite effects in flurothyl seizures. Muscimol infused into the anterior region is anticonvulsant while similar infusions into the posterior region are proconvulsant. These two regions differ morphologically, and utilize different efferent networks. In contrast, in postnatal day 15 male rats, there is no such differentiation and muscimol infusions have only proconvulsant effects. The hallmark of the female substantia nigra pars reticulata is the fact that muscimol- mediated proconvulsant effects cannot be demonstrated in any region at any age. The sex-related difference in nigral seizure control may be related to the lack of testosterone in females. Accordingly, neonatal castration of males results in the loss of the proconvulsant region. The male type of the substantia nigra pars reticulata effects can be induced by exogenous testosterone administration in neonatally castrated male or in female rats. The phenotype of nigral GABAergic neurons, as characterized by GABAA receptor subunit composition, muscimol-induced electrophysiological responses, and connectivity of output networks may each be altered by the presence of testosterone. Better understanding of the influence of the endocrine system on brain development and neuronal activity may provide new insight into the treatment of age- and sex-dependent seizure disorders.

Animals↗

Stochastic resonance with differential code in feedforward network with intra-layer random connections.

We examined stochastic resonance with a differential coding scheme using a multilayer feedforward neural network which is composed of intra-layer connections. We show that the network, with random synaptic connections in each layer, encodes an input signal into a spike coherence that represents temporal differences among the inputs. We also demonstrate that both internal and external noise enhance the detection of weak signals. Finally, we discuss how the feedforward network with intra-layer random connections is similar to a membrane in its sensitivity to and amplification of a change in stimulus and suggest that the intensity of internal noise may be tuned in a real brain.

Computer Simulation↗

Diffusion tensor magnetic resonance imaging tractography in cognitive disorders.

PURPOSE OF REVIEW: The advent of novel techniques for tracing connections in vivo, such as diffusion tensor magnetic resonance imaging tractography, allows us, for the first time in the human brain, to study the microstructural integrity of white matter fibres and perform virtual dissections of large scale neurocognitive networks. This review will outline the advantages and limitations of applying diffusion tensor magnetic resonance imaging to the study of cognitive and behavioural disorders in neurology and psychiatry. RECENT FINDINGS: Diffusion tensor magnetic resonance imaging has been used to re-explore the anatomy of white matter tracts in the living human brain and to create connectional models of brain function. Beyond its application to classical disconnection syndromes, diffusion tensor magnetic resonance imaging is becoming an important tool to extend the disconnectionist paradigm to neurodevelopmental and neurodegenerative disorders. SUMMARY: For the first time, we are able to correlate disconnecting lesions with clinical symptoms in vivo and test the disconnection mechanism directly in cognitive disorders. With diffusion tensor magnetic resonance imaging tractography alone and in combination with other magnetic resonance imaging techniques, researchers are able to detect abnormalities in white matter that are not visible with conventional magnetic resonance imaging.

Anisotropy↗

The effects of anesthetics on brain activity and cognitive function.

PURPOSE OF THIS REVIEW: This review presents an overview of recent findings related to changes in brain activity with increasing anesthesia mainly obtained with brain imaging and electrophysiological techniques in humans. RECENT FINDINGS: Recent studies have revealed that the brain as a whole is not affected to the same degree by anesthetics, but that specific brain regions (and particular cognitive processes mediated by these regions) are more sensitive to anesthesia and sedation than others. Inhibition of activity in multimodal association cortices (such as parietal and prefrontal association cortices) by sedative concentrations of anesthetics produces amnesia and attention deficits, whereas activity in unimodal cortices and in the thalamus remains largely unaffected by low doses of anesthetics. Activity in the midbrain reticular formation, thalamus, and unimodal cortices appears to be suppressed only by anesthetic concentrations causing unconsciousness. Besides those regional suppressive effects, anesthetics impair functional connections between neurons in distributed cortical and thalamocortical networks, which also contributes to the state of anesthesia. SUMMARY: Anesthetics produce changes in the patient's behavioral state by interacting with brain activity via at least two mechanisms: the dose-dependent global and regionally specific suppression of neuronal activity and the disruption of functional interactivity within distributed neural networks.

Journal Article↗

Extracellular matrix alterations in brains lacking four of its components.

The organization of the brain extracellular matrix appears to be based on aggregates of hyaluronan and proteoglycans, connected by oligomeric glycoproteins. Mild phenotypical consequences were reported from several mouse strains lacking components of this matrix such as neurocan, brevican, tenascin-R, and tenascin-C. To further challenge the flexibility of the extracellular matrix network of the brain, mice lacking all four brain extracellular matrix molecules were generated, which were found to be viable and fertile. Analysis of the brains of 1-month-old quadruple KO mice revealed increased protein levels of fibulin-1 and fibulin-2. Histochemical analysis showed an unusual parenchymal deposition of these fibulins. The quadruple KO mice also displayed obvious changes in the pattern of deposition of hyaluronan. Further, an almost quadruple knockout like extracellular environment was noticed in the brains of triple knockout mice lacking both tenascins and brevican, since these brains had strongly reduced levels of neurocan.

Animals↗

Matrix metalloproteinase induction by EMMPRIN in experimental focal cerebral ischemia.

Focal cerebral ischemia leads to the gradual disruption of the extracellular matrix. A key role in the turnover of the extracellular matrix is played by the system of matrix metalloproteinases (MMPs). In this study we describe changes of the MMP inducer protein (EMMPRIN) following experimental cerebral ischemia (induced for 3 h and followed by 24 h reperfusion, suture model) in rats. Extracellular EMMPRIN was measured by Western blot of the ischemic and nonischemic basal ganglia and cortex separately. Compared with the contralateral nonischemic area, the ischemic hemisphere showed a significant increase in EMMPRIN: basal ganglia, 158% +/- 4% (P < 0.05); cortex, 128% +/- 25% (P < 0.05). Immunohistochemistry was used to localize EMMPRIN on cerebral microvessels. EMMPRIN-positive microvascular structures were quantified by automatic morphometric video-imaging analysis and a significant increase in the number of cerebral microvessels staining positive for EMMPRIN in the ischemic basal ganglia was shown. The significant loss of microvascular basal lamina antigen collagen type IV in ischemic cortex and basal ganglia was calculated by Western blot. Measured by gelatin zymography, we demonstrated an MMP-2 and MMP-9 increase in the ischemic brain regions (P < 0.05). For the first time the MMP activation system EMMPRIN was shown to be relevant in cerebral ischemia. These results raise the possibility that the increased expression of EMMPRIN, the increase in MMPs and the damage of the basal lamina following cerebral ischemia are connected and part of a network of related changes.

Animals↗

Functional connectivity in fMRI: A modeling approach for estimation and for relating to local circuits.

Although progress has been made in relating neuronal events to changes in brain metabolism and blood flow, the interpretation of functional neuroimaging data in terms of the underlying brain circuits is still poorly understood. Computational modeling of connection patterns both among and within regions can be helpful in this interpretation. We present a neural network model of the ventral visual pathway and its relevant functional connections. This includes a new learning method that adjusts the magnitude of interregional connections in order to match experimental results of an arbitrary functional magnetic resonance imaging (fMRI) data set. We demonstrate that this method finds the appropriate connection strengths when trained on a model system with known, randomly chosen connection weights. We then use the method for examining fMRI results from a one-back matching task in human subjects, both healthy and those with schizophrenia. The results discovered by the learning method support previous findings of a disconnection between left temporal and frontal cortices in the group with schizophrenia and a concomitant increase of right-sided temporo-frontal connection strengths. We then demonstrate that the disconnection may be explained by reduced local recurrent circuitry in frontal cortex. This method extends currently available methods for estimating functional connectivity from human imaging data by including both local circuits and features of interregional connections, such as topography and sparseness, in addition to total connection strengths. Furthermore, our results suggest how fronto-temporal functional disconnection in schizophrenia can result from reduced local synaptic connections within frontal cortex rather than compromised interregional connections.

Brain↗

Functional connectivity in human cortical motor system: a cortico-cortical evoked potential study.

In order to understand the complex functional organization of the motor system, it is essential to know the anatomical and functional connectivity among individual motor areas. Clinically, knowledge of these cortico-cortical connections is important to understand the rapid spread of epileptic discharges through the network underlying ictal motor manifestation. In humans, however, knowledge of neuronal in vivo connectivity has been limited. We recently reported a new method, 'cortico-cortical evoked potential (CCEP)', to electrically track the cortico-cortical connections by stimulating a part of the brain through subdural electrodes and recording the cortical evoked potentials that emanate from a distant region of the cortex via neuronal projections. We applied the CCEP methodology to investigate in vivo cortico-cortical connections between the lateral motor cortex [LMCx; sensorimotor (SM) and lateral premotor areas] and the medial motor cortex [MMCx; supplementary motor area proper (SMA), pre-SMA and foot SM]. Seven patients with intractable partial epilepsy were studied. These patients had chronic implantation of subdural electrodes covering part of the lateral and medial frontal areas. As a part of the routine pre-surgical evaluation, comprehensive cortical mapping was performed by electrical stimulation of the subdural electrodes, and the precise localization of the subdural electrodes was defined by MRI co-registration. Single-pulse electrical stimuli were delivered to MMCx (7 patients) and LMCx (4), and CCEPs time-locked to the stimuli were recorded by averaging electrocorticograms from LMCx and MMCx, respectively. Short-latency CCEPs were observed when stimulating MMCx and recording from LMCx (mean latency: 21.6 ms, range: 9-47 ms) and vice versa when stimulating LMCx and recording from MMCx (mean latency: 29.4 ms, range: 11-57 ms). In terms of the location of these stimulus sites and CCEP responses along the rostrocaudal axis, regression analysis revealed a consistent correlation between the sites of stimulation and maximum CCEP for stimulation of both MMCx and LMCx. Functionally, stimulation of the positive motor areas in MMCx elicited CCEPs at the somatotopically homologous regions in LMCx (71%). The same findings were observed in MMCx (82%) upon stimulation of LMCx. In four subjects in whom bi-directional connectivity was investigated by stimulating both MMCx and LMCx, reciprocality was observed in the majority of connections (78-94%). In conclusion, the present study demonstrated a human motor cortico-cortical network connecting (i) anatomically homologous areas of LMCx and MMCx along the rostrocaudal cognitive-motor gradient; and (ii) somatotopically homologous regions in LMCx and MMCx in a reciprocal manner.

Adolescent↗