Gene expression profiles of ileal inflammatory bowel disease correlate with disease phenotype and advance understanding of its immunopathogenesis.

BACKGROUND: Pouchitis may develop in patients with ulcerative colitis undergoing pouch surgery. We aimed to evaluate the de novo inflammation developing in the ileal pouch, hypothesizing that it may be similar to ileitis in Crohn's disease (CD). METHODS: Patients with ulcerative colitis pouch were prospectively recruited, stratified according to disease behavior into normal pouch, chronic pouchitis, and Crohn's-like disease of the pouch groups, and compared with controls. Gene expression analysis was performed using microarrays, validated by real-time polymerase chain reaction. Gene ontology and clustering were evaluated using bioinformatic tools. RESULTS: Sixty-six subjects were recruited. Although in ulcerative colitis ileum there were no significant gene expression alterations, patients with normal pouch had 168 significant alterations (fold change ≥ 2, corrected P ≤ 0.05). In chronic pouchitis and Crohn's-like disease of the pouch, 490 and 1152 alterations were detected, respectively. High degree of overlap in gene expression alterations between the pouch subgroups was demonstrated. The magnitude of change correlated with pouch disease behavior. Gene expression profiles were more reflective of disease behavior compared with inflammatory indices. CD ileitis had 358 alterations, with a 90% overlap with pouchitis. Gene ontology analyses revealed multiple biological processes associated with pouch inflammation, including response to chemical stimulus, small molecule metabolic and immune system processes, and specific infection-related pathways such as Staphylococcus aureus, leishmaniasis, and tuberculosis. CONCLUSIONS: Gene alterations in pouch inflammation and CD overlap, suggesting that inflammatory bowel diseases is a spectrum, rather than distinct diseases. Pouchitis may serve as a model of CD. The novel pathways associated with inflammatory bowel diseases may decipher pathophysiology and suggest targets for intervention.

Population responses to contour integration: early encoding of discrete elements and late perceptual grouping.

The neuronal mechanisms underlying perceptual grouping of discrete, similarly oriented elements are not well understood. To investigate this, we measured neural population responses using voltage-sensitive dye imaging in V1 of monkeys trained on a contour-detection task. By mapping the contour and background elements onto V1, we could study their neural processing. Population response early in time showed activation patches corresponding to the contour/background individual elements. However, late increased activity in the contour elements, along with suppressed activity in the background elements, enabled us to visualize in single trials a salient continuous contour "popping out" from a suppressed background. This modulated activity in the contour and in background extended beyond the cortical representation of individual contour or background elements. Finally, the late modulation was correlated with behavioral performance of contour saliency and the monkeys' perceptual report. Thus, opposing responses in the contour and background may underlie perceptual grouping in V1.

Collinear stimuli induce local and cross-areal coherence in the visual cortex of behaving monkeys.

BACKGROUND: Collinear patterns of local visual stimuli are used to study contextual effects in the visual system. Previous studies have shown that proximal collinear flankers, unlike orthogonal, can enhance the detection of a low contrast central element. However, the direct neural interactions between cortical populations processing the individual flanker elements and the central element are largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Using voltage-sensitive dye imaging (VSDI) we imaged neural population responses in V1 and V2 areas in fixating monkeys while they were presented with collinear or orthogonal arrays of Gabor patches. We then studied the spatio-temporal interactions between neuronal populations processing individual Gabor patches in the two conditions. Time-frequency analysis of the stimulus-evoked VSDI signal showed power increase mainly in low frequencies, i.e., the alpha band (α; 7-14 Hz). Power in the α-band was more discriminative at a single trial level than other neuronal population measures. Importantly, the collinear condition showed an increased intra-areal (V1-V1 and V2-V2) and inter-areal (V1-V2) α-coherence with shorter latencies than the orthogonal condition, both before and after the removal of the stimulus contribution. α-coherence appeared between discrete neural populations processing the individual Gabor patches: the central element and the flankers. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that collinear effects are mediated by synchronization in a distributed network of proximal and distant neuronal populations within and across V1 and V2.

Spatiotemporal effects of microsaccades on population activity in the visual cortex of monkeys during fixation.

During visual fixation, the eyes make fast involuntary miniature movements known as microsaccades (MSs). When MSs are executed they displace the visual image over the retina and can generate neural modulation along the visual pathway. However, the effects of MSs on neural activity have substantial variability and are not fully understood. By utilizing voltage-sensitive dye imaging, we imaged the spatiotemporal patterns induced by MSs in V1 and V2 areas of behaving monkeys while they were fixating and presented with visual stimuli. We then investigated the neuronal modulation dynamics, induced by MSs, under different visual stimulation. MSs induced monophasic or biphasic neural responses depending on stimulus size. These neural responses were accompanied by different spatiotemporal patterns of synchronization. Finally, we show that a local patch of population response evoked by a small stimulus was clearly shifted over the V1 retinotopic map after each MS. Our results demonstrate the lack of visual stability in V1 following MSs and help clarify the substantial variability reported for MSs effects on neuronal responses. The observed neural effects suggest that MSs are associated with a continuum of neuronal responses in V1 area reflecting diverse spatiotemporal dynamics.

Precise spatiotemporal patterns among visual cortical areas and their relation to visual stimulus processing.

Visual processing shows a highly distributed organization in which the presentation of a visual stimulus simultaneously activates neurons in multiple columns across several cortical areas. It has been suggested that precise spatiotemporal activity patterns within and across cortical areas play a key role in higher cognitive, motor, and visual functions. In the visual system, these patterns have been proposed to take part in binding stimulus features into a coherent object, i.e., to be involved in perceptual grouping. Using voltage-sensitive dye imaging (VSDI) in behaving monkeys (Macaca fascicularis, males), we simultaneously measured neural population activity in the primary visual cortex (V1) and extrastriate cortex (V2, V4) at high spatial and temporal resolution. We detected time point population events (PEs) in the VSDI signal of each pixel and found that they reflect transient increased neural activation within local populations by establishing their relation to spiking and local field potential activity. Then, we searched for repeating space and time relations between the detected PEs. We demonstrate the following: (1) spatiotemporal patterns occurring within (horizontal) and across (vertical) early visual areas repeat significantly above chance level; (2) information carried in only a few patterns can be used to reliably discriminate between stimulus categories on a single-trial level; (3) the spatiotemporal patterns yielding high classification performance are characterized by late temporal occurrence and top-down propagation, which are consistent with cortical mechanisms involving perceptual grouping. The pattern characteristics and the robust relation between the patterns and the stimulus categories suggest that spatiotemporal activity patterns play an important role in cortical mechanisms of higher visual processing.

Population response to contextual influences in the primary visual cortex.

Collinear proximal flankers can facilitate the detection of a low-contrast target or generate false-alarm target detection in the absence of a target. Although these effects are known to involve subthreshold neuronal interactions beyond the classical receptive field, the underlying neuronal mechanisms are not fully understood. Here, we used voltage-sensitive dye imaging that emphasizes subthreshold population activity, at high spatial and temporal resolution and imaged the visual cortex of fixating monkeys while they were presented with a low-contrast Gabor target, embedded within collinear or orthogonal flankers. We found that neuronal activity at the target site in area primary visual cortex increased and response latency decreased due to spatial spread of activation from the flankers' site. This increased activity was smaller than expected by a linear summation. The presentation of flankers alone induced strong spatial filling-in at the target site. Importantly, the increased neuronal activity at the target site was synchronized over time, both locally and with neuronal population at the flanker's site. This onset synchronization was higher for collinear than for orthogonal flankers. We further show that synchrony is a superior code over amplitude, for discriminating collinear from orthogonal pattern. These results suggest that population synchrony can serve as a code to discriminate contextual effects.

Effect of hyperbaric oxygenation on brain hemodynamics, hemoglobin oxygenation and mitochondrial NADH.

To determine the HbO(2) oxygenation level at the microcirculation, we used the hyperbaric chamber. The effects of hyperbaric oxygenation (HBO) were tested on vitality parameters in the brain at various pressures. Microcirculatory hemoglobin oxygen saturation (HbO(2)), cerebral blood flow (CBF) and mitochondrial NADH redox state were assessed in the brain of awake restrained rats using a fiber optic probe. The hypothesis was that HBO may lead to maximal level in microcirculatory HbO(2) due to the amount of the dissolved O(2) to provide the O(2) consumed by the brain, and therefore no O(2) will be dissociated from the HbO(2). Awake rats were exposed progressively to 15 min normobaric hyperoxia, 100% O(2) (NH) and to 90 min hyperbaric hyperoxia (HH) from 1.75 to 6.0 absolute atmospheres (ATA). NH and HH gradually decreased the blood volume measured by tissue reflectance and NADH but increased HbO(2) in relation to pO(2) in the chamber up to a nearly maximum effect at 2.5 ATA. Two possible approximations were found to describe the relationship between NADH and HbO(2): linear or logarithmic. These findings show that the increase in brain microcirculatory HbO(2) is due to an increase in O(2) supply by dissolved O(2), reaching a maximum at 2.5 ATA. NADH is oxidized (decreased signal) in parallel to the HbO(2) increase, showing maximal tissue oxygenation and cellular mitochondrial NADH oxidation at 2.5 ATA. In conclusion, in the normoxic brain, the level of microcirculatory HbO(2) is about 50% as compared to the maximal level recorded at 2.5 ATA and the minimal level measured during anoxia.