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Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert.

BACKGROUND: Extinction of conditioned fear is thought to form a new safety memory that is expressed in the context in which the extinction learning took place. Rodent studies implicate the ventromedial prefrontal cortex (vmPFC) and hippocampus in extinction recall and its modulation by context, respectively. The aim of the present study is to investigate the mediating anatomy of extinction recall in healthy humans. METHODS: We used event-related functional magnetic resonance imaging (fMRI) and a 2-day fear conditioning and extinction protocol with skin conductance response as the index of conditioned responses. RESULTS: During extinction recall, we found significant activations in vmPFC and hippocampus in response to the extinguished versus an unextinguished stimulus. Activation in these brain regions was positively correlated with the magnitude of extinction memory. Functional connectivity analysis revealed significant positive correlation between vmPFC and hippocampal activation during extinction recall. CONCLUSIONS: These results support the involvement of the human hippocampus as well as vmPFC in the recall of extinction memory. Furthermore, this provides a paradigm for future investigations of fronto-temporal function during extinction recall in psychiatric disorders such as posttraumatic stress disorder.

Adult↗

Neuropathological studies of synaptic connectivity in the hippocampal formation in schizophrenia.

Cytoarchitectural changes in the hippocampal formation have been prominent among the various neuropathological abnormalities reported in schizophrenia. Replicated positive findings include decreased neuronal size and alterations in presynaptic and dendritic markers. These findings, in the absence of neurodegenerative changes, suggest that there are alterations in the neural circuitry in schizophrenia. These may represent the anatomical correlate of the aberrant functional connectivity described in neuroimaging studies, which in turn contributes to the psychotic and cognitive symptomatology of the disorder. The identity of the affected hippocampal circuits remains unclear; there is evidence for both glutamatergic and GABAergic involvement, and perhaps for a gradient of pathology in which changes are most apparent in CA4 and the subiculum, and least in CA1. The data, their interpretation, and their limitations are discussed, with particular emphasis upon molecular and immunological studies of synaptic protein gene expression.

Hippocampus↗

The PS2 integrin ligand tiggrin is required for proper muscle function in Drosophila.

Tiggrin is a novel extracellular matrix ligand for the Drosophila PS2 integrins. We have used flanking P elements to generate a precise deletion of tiggrin. Most flies lacking tiggrin die as larvae or pupae. A few adults do emerge and these appear to be relatively normal, displaying only misshapen abdomens and a low frequency of wing defects. Examination of larvae shows that muscle connections, function and morphology are defective in tiggrin mutants. Muscle contraction waves that extend the length of the larvae are much slower in tiggrin mutants. Direct examination of bodywall muscles shows defects in muscle attachment sites, where tiggrin is specifically localized, and muscles appear thinner. Transgenes expressing tiggrin are capable of rescuing tiggrin mutant phenotypes. Transgenes expressing a mutant tiggrin, whose Arg-Gly-Asp (RGD) integrin recognition sequence has been mutated to Leu-Gly-Ala (LGA) show much reduced, but significant, rescuing ability. Cell spreading assays detect no interactions of this mutant tiggrin with PS2 integrins. Therefore, while the RGD sequence is critical for PS2 interactions and full activity in the whole fly, the mutant tiggrin retains some function(s) that are probably mediated by interactions with other ECM molecules or cell surface receptors

Abdomen↗

["Conditioned states" of cortical cells].

Experimental data are presented on reorganizations of intra- and interanalyzer functional connections of neurones in the course of conditioning, by interval cross-histograms of two impulse series, and notions on neuronal organization of local and spread conditioned states are formulated. Numerous varieties of the analysis of systemic, interconnected activity of cortical neurones in the process of learning convince of the fact that individual and integrative neuronal functions characterize different qualitative levels of their activity. The integrative function of neurones shows various degrees of complicacy and specialization. The local conditioned state is considered to represent functional integration of neurones in cortical microregions, and the spread conditioned state--as neuronal integration between cortical projection zones. The interaction of neurones in the cortical projection of conditioned stimulus is more multiform and complex than that in the motor cortex. During the elaboration of inhibitory conditioned reflex there occurs a reorganization of the cortical systemic activity in the projection zone of the conditioned stimulus and a decrease of intensity of distant connections.

Animals↗

Hypnosis decouples cognitive control from conflict monitoring processes of the frontal lobe.

Hypnosis can profoundly alter sensory awareness and cognitive processing. While the cognitive and behavioral phenomena associated with hypnosis have long been thought to relate to attentional processes, the neural mechanisms underlying susceptibility to hypnotic induction and the hypnotic condition are poorly understood. Here, we tested the proposal that highly hypnotizable individuals are particularly adept at focusing attention at baseline, but that their attentional control is compromised following hypnosis due to a decoupling between conflict monitoring and cognitive control processes of the frontal lobe. Employing event-related fMRI and EEG coherence measures, we compared conflict-related neural activity in the anterior cingulate cortex (ACC) and control-related activity in the lateral frontal cortex (LFC) during Stroop task performance between participants of low and high hypnotic susceptibility, at baseline and after hypnotic induction. The fMRI data revealed that conflict-related ACC activity interacted with hypnosis and hypnotic susceptibility, in that highly susceptible participants displayed increased conflict-related neural activity in the hypnosis condition compared to baseline, as well as with respect to subjects with low susceptibility. Cognitive-control-related LFC activity, on the other hand, did not differ between groups and conditions. These data were complemented by a decrease in functional connectivity (EEG gamma band coherence) between frontal midline and left lateral scalp sites in highly susceptible subjects after hypnosis. These results suggest that individual differences in hypnotic susceptibility are linked with the efficiency of the frontal attention system, and that the hypnotized condition is characterized by a functional dissociation of conflict monitoring and cognitive control processes.

Adult↗

Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk. Focal dysfunction and distributed disconnectivity reappraised.

BACKGROUND: PET studies of verbal fluency in schizophrenia report a failure of 'deactivation' of left superior temporal gyrus (STG) in the presence of activation of left dorsolateral prefrontal cortex (DLPFC), which deficit has been attributed to underlying 'functional disconnectivity'. AIM: To test whether these findings provide trait-markers for schizophrenia. METHOD: We used H2(15)O PET to examine verbal fluency in 10 obligate carriers of the predisposition to schizophrenia, 10 stable patients and 10 normal controls. RESULTS: We found no evidence of a failure of left STG deactivation in carriers or patients. Instead, patients failed to deactivate the precuneus relative to other groups. We found no differences in functional connectivity between left DLPFC and left STG but patients exhibited significant disconnectivity between left DLPFC and anterior cingulate cortex. CONCLUSIONS: Failure of left STG 'deactivation' and left fronto-temporal disconnectivity are not consistent findings in schizophrenia; neither are they trait-markers for genetic risk. Prefrontal functional disconnectivity here may characterise the schizophrenic phenotype.

Heterozygote↗

Tracing of axonal connectivities in a combined slice preparation of rat brains--a study by rhodamine-dextran-amine-application in the lateral nucleus of the amygdala.

In preparation for electrophysiological studies, the fiber pathways within the amygdala of rats have been examined using a combined Nissl- and silver-staining method (Bielshowsky) in horizontal sections of the amygdala. To determine if fibers in the lateral nucleus of the amygdala are in functional connection with other brain regions, an anterograde and retrograde axonal tracing method (application of rhodamine-dextran-amine) was performed. Horizontal slices containing some nuclei of the amygdala (lateral nucleus, basolateral nucleus, central nucleus, medial nucleus), as well as the entorhinal cortex, the hippocampus and parts of the piriform cortex were used. Crystals of rhodamine-dextran-amine were placed in the lateral nucleus. Intra-amygdaloid connections as well as connections to other brain regions were preserved in this preparation. The connectivities of the lateral nucleus with other nuclei of the amygdala (basolateral, medial, central) correspond with the findings made by tracer applications in-vivo. The use of a tracer that is transported in both the antero- and retrograde direction shows the whole spectrum of efferent and afferent fibers which are involved in the projection pattern of the lateral nucleus. To test the usefulness of this preparation for electrophysiological studies, extracellular field potentials were recorded.

Amygdala↗

Quantitative [14C]2-deoxyglucose study of a functional dissociation between anterior and posterior cingulate cortices in mice.

We have previously shown that lesion of the posterior cingulate cortex (CCP) but not of the anterior cingulate cortex (CCA), produced learning and memory deficits. As a first evaluation of the functional anatomical basis of this dissociation, we used the quantitative [14C]2-deoxyglucose method and electrical brain stimulation to determine the functional connections of the CCA and CCP in mice. CCP stimulation (but not CCA stimulation) produced significant metabolic increases in the hippocampal formation and in the subicular complex. This result is consistent with the hypothesis that learning and memory deficits following CCP lesion may be due to the disruption of functional neural pathways between the CCP and hippocampal structures.

Animals↗

Repetitive transcranial magnetic stimulation to improve mood and motor function in Parkinson's disease.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that can produce lasting changes in excitability and activity in cortical regions underneath the stimulation coil (local effect), but also within functionally connected cortical or subcortical regions (remote effects). Since the clinical presentation of Parkinson's disease (PD) is related to abnormal neuronal activity within the basal ganglia and cortical regions, including the primary motor cortex, the premotor cortex and the prefrontal cortex, several studies have used rTMS to improve brain function in PD. Here, we review the studies that have investigated the possible therapeutic effects of rTMS on mood and motor function in PD patients. We highlight some methodological inconsistencies and problems, including the difficulty to define the most effective protocol for rTMS or to establish an appropriate placebo condition. We finally propose future directions of research that may help to improve the therapeutic efficacy of rTMS in PD.

Affect↗

Effect of aging on the modulation of macrophage functions by neuropeptides.

The existence of a functional connection between the nervous and the immune system is supported by increasing recent evidence. In previous work we have shown that peptides from the nervous system, such as gastrin-releasing peptide (GRP), neuropeptide Y (NPY) and sulfated cholecystokinin octapeptide (CCK-8s), have modulatory effects on the immune functions in adult animals. Since the immunodepression found in aging organisms may be related to changes in the neuroimmune network, the aim of the present work was to study the changes with aging in the effect of CCK-8s, GRP and NPY on peritoneal macrophage functions (adherence to tissues, mobility, ingestion of foreign particles and superoxide anion production) from BALB/c mice of three different ages: adult (24+/-2 weeks old), mature (50+/-2 weeks old) and old (72+/-2 weeks old). The results show that the increase in adherence capacity produced by neuropeptides in cells from adult and mature animals disappears in old mice. The stimulatory effect of GRP and NPY on mobility, ingestion and superoxide production in macrophages from adult mice disappears (GRP) or changes to inhibition (NPY) in cells from old animals. The decrease of these functions caused by CCK-8s in adult or mature animals continues in old mice. These data suggest that the modulation by neuropeptides of the macrophage function changes with the age of animals.

Aging↗

[Strategies for data analysis of brain activation studies with functional MR tomography].

The sensitivity of gradient-echo magnetic resonance imaging (MRI) to changes in cerebral blood oxygenation has been introduced for mapping functional brain activation. To benefit from the high spatial and temporal resolution of the respective dynamic MRI data sets, their analysis requires algorithms that are capable of both precisely delineating task-related activation patterns and demonstrating functional connectivity of interacting areas. Here, we present various strategies for data evaluation by means of correlational analyses that surpass the quality of subtraction-based activation maps by improving both sensitivity and robustness. On a pixel-by-pixel basis the approach correlates signal time courses with a reference function, reflecting the temporal sequence of activated and control states. Extended versions employ the calculation of auto- or cross-correlation functions that increase sensitivity, but require periodic stimulations. Following individual correction for non-specific but correlated signal fluctuations, mapping of task-related coherent activation can be improved using neighborhood principles. Such refined strategies are expected to enhance the usefulness of oxygenation-sensitive MRI for studying the functional anatomy of the human brain under both physiological and pathological conditions.

Algorithms↗

Beyond the epithelium: cadherin function in fibrous connective tissues.

In fibrous connective tissues, fibroblasts are organized into syncytia, cellular networks that enable matrix remodeling and that are interconnected by intercellular adherens junctions (AJs). The AJs of fibroblasts are mediated by N-cadherin, a broadly expressed classical cadherin that is critically involved in developmental processes, wound healing and several diseases of mesenchymal tissues. In contrast to E-cadherin-dependent junctions of epithelia, the formation of AJs in fibrous connective tissues is relatively uncharacterized. Work over the last several years has documented an expanding list of molecules which function to regulate N-cadherin mediated junctions such as: Fer, PTP1B, cortactin, calcium, gelsolin, PIP5KIgamma, PIP2, and the Rho family of GTPases. We present an overview on the regulation of N-cadherin-mediated junction formation that highlights recent molecular advances in the field and rationalizes the roles of N-cadherin in connective tissue function.

Adherens Junctions↗

Developmental expression of MNAR mRNA in the mouse brain.

During the development of the central nervous system, estrogen influences cellular differentiation and determines the functional connectivity of distinct neural networks. Estrogens generally act through nuclear estrogen receptors (ERs). Recent research has additionally revealed rapid estrogen effects requiring the binding of estrogen to membrane/cytoplasmic ERs and the activation of intracellular signaling systems such as the Src/MAPK cascade. The scaffold protein MNAR/PELP1 appears to be the designated functional mediator of such non-genomic estrogen effects between non-nuclear ERs and Src/MAPKs. In this study, we demonstrate the expression and differential regulation of MNAR mRNA in the developing male and female mouse brain by quantitative polymerase chain reaction. In the midbrain and hypothalamus, a gradual decline in MNAR mRNA levels has been observed prenatally with the highest values at embryonic day 15 and lowest at postnatal day 15. In the cortex, mRNA levels do not fluctuate until postnatal day 7 but decrease thereafter. No differences in MNAR expression between sexes have been detected. Analysis of neuronal and astroglia-enriched cell cultures has revealed the presence of MNAR in both cell types.

Animals↗

Interaction of the two frontal eye fields before saccade onset.

A normal environment often contains many objects of interest that compete to attract our gaze. Nevertheless, instead of initiating a flurry of conflicting signals, central populations of oculomotor neurons always seem to agree on the destination of the next saccade. How is such a consensus achieved? In a unit recording and microstimulation study on trained monkeys, we sought to elucidate the mechanism through which saccade-related cells in the frontal eye fields (FEF) avoid issuing competing commands. Presaccadic neuronal activity was recorded in one FEF while stimulating the contralateral FEF with low-intensity currents that evoked saccades. When an eye-movement cell was isolated, we determined: the movement field of the cell, the cell's response to contralateral FEF microstimulation, the cell's response when the evoked saccade was in the preferred direction of the cell (using the collision technique to deviate appropriately the evoked saccade vector), and the cell's response to a stimulation applied during a saccade in the cell's preferred direction, to reveal a possible inhibitory effect. Complete results were obtained for 71 stimulation-recording pairs of FEF sites. The unit responses observed were distributed as follows: 35% of the cells were unaffected, 37% were inhibited, and 20% excited by contralateral stimulation. These response types depended on the site of contralateral stimulation and did not vary when saccades were redirected by collision. This invariant excitation or inhibition of cells, seemingly due to hardwired connections, depended on the angular difference between their preferred vector and the vector represented by the cells stimulated. By contrast, 8% of the cells were either activated or inhibited depending on the vector of the saccade actually evoked by collision. These results suggest that the consensus between cells of oculomotor structures at the time of saccade initiation is implemented by functional connections such that the cells that command similar movements mutually excite each other while silencing those that would produce conflicting movements. Such a rule would be an effective implementation of a winner-take-all mechanism well suited to prevent conflicts.

Animals↗

[Tractography of the visual pathways: routine examination in magnetic resonance imaging].

Water diffusion analysis in magnetic resonance imaging (MRI) provides an elective visualization of fiber tract orientations in cerebral white matter, especially for optic tracts. We explored 25 patients from 18 to 45 years of age, with normal MRI in 20 subjects, and radiological anomalies in five. On a 1.5 Tesla MRI apparatus, diffusion tensor acquisitions were performed in 5 minutes 58 seconds with an EPI Single Shot sequence covering the entire brain. Image displacements were precluded by patient information and adequate fixation, then digitally corrected on workstations. Volume merging and fiber tract extraction were achieved using dedicated software (Volume-One and dTV). A directional depiction was obtained for all areas in the white matter, in particular for white matter junctions. Coming from the lateral geniculate body, the optic tracts were directed posteriorly toward the occipital cortex, with numerous connections to extrastriate associative areas, and through the corpus callosum and the fornix. Diffusion tractography requires optimization of volume displacements, before and secondary to MRI acquisitions. Our diffusion tensor acquisition, with image optimization in a short-duration sequence can be routinely applied to all patients, for a specific analysis of functional connections between cortical areas of cerebral white matter.

Adolescent↗

Is there a molecular connection between hypoxia and aging?

Aging is associated with high incidence of ischemic diseases, which go along with a drop in tissue oxygenation. At the molecular level the hypoxia inducible factor (HIF) is the master regulator for hypoxia-induced gene expression. Recent studies demonstrated age-related changes in the HIF system, which might explain the reduced ability to cope with hypoxia in elderly. There are also some evidences that HIF is functionally connected to the aging process itself.

Aging↗

Deterministic dynamics emerging from a cortical functional architecture.

Cerebral cortex has a range of interconnected functional architectures. Some appear random and without structure, while others are geometrical. Although the biological details certainly constrain spatial temporal patterns in neural networks, the influence that the laws of deterministic dynamics bring to bear on even isolated simple geometries are unknown. Layer II/III of primary visual cortex has long range horizontal connections with projections to and from other layers. The long range excitatory connections were modeled in isolation as an isolated laterally connected functional architecture. The Hodgkin-Huxley or Pinsky-Rinzel equations were used to simulate the neuronal elements. Waves of activity could propagate through the functional architecture; depending on the synaptic kinetics, the system could settle down into quiescence, oscillations, or seemingly random behavior. Order could be found in random-looking behavior by the application of techniques from chaos theory. Furthermore, the range and transitions of the temporal patterns in the modeled collection of neurons are similar to those found in other non-linear systems. The possibility that the temporal patterns of neurons in situ are also constrained by these mathematical laws is discussed.

Action Potentials↗

[A new form of caudate inhibition in electrostimulation of the deep structures of the human brain].

In patients treated with implanted electrodes, the inhibitory matrices of artificial stable functional connections (ASFC) were formed by means of synchronous electrical stimulation of the neuronal units of the 2nd type (links of the ASFC chain) and the caudate nucleus. The matrices in certain neuronal pools of subcortical formations were characterized by selectiveness, stability, steadiness and had an "input" organized by a special code: the functional mark. Transfer of functional characteristics of the inhibitory matrix from one neuronal unit of the 2nd type to another within the same cerebral hemisphere or from one hemisphere to another corroborates the fact that it has been formed.

Adult↗