The laminar organization of cell types in macaque cortex and its relationship to neuronal oscillations.

The canonical microcircuit (CMC) has been hypothesized to be the fundamental unit of information processing in cortex. Each CMC unit is thought to be an interconnected column of neurons with specific connections between excitatory and inhibitory neurons across layers. Recently, we identified a conserved spectrolaminar motif of oscillatory activity across the primate cortex that may be the physiological consequence of the CMC. The spectrolaminar motif consists of local field potential (LFP) gamma-band power (40-150 Hz) peaking in superficial layers 2 and 3 and alpha/beta-band power (8-30 Hz) peaking in deep layers 5 and 6. Here, we investigate whether specific conserved cell types may produce the spectrolaminar motif. We collected laminar histological and electrophysiological data in 11 distinct cortical areas spanning the visual hierarchy: V1, V2, V3, V4, TEO, MT, MST, LIP, 8A/FEF, PMD, and LPFC (area 46), and anatomical data in DP and 7A. We stained representative slices for the three main inhibitory subtypes, Parvalbumin (PV), Calbindin (CB), and Calretinin (CR) positive neurons, as well as pyramidal cells marked with Neurogranin (NRGN). We found a conserved laminar structure of PV, CB, CR, and pyramidal cells. We also found a consistent relationship between the laminar distribution of inhibitory subtypes with power in the local field potential. PV interneuron density positively correlated with gamma (40-150 Hz) power. CR and CB density negatively correlated with alpha (8-12 Hz) and beta (13-30 Hz) oscillations. The conserved, layer-specific pattern of inhibition and excitation across layers is therefore likely the anatomical substrate of the spectrolaminar motif. Significance Statement: Neuronal oscillations emerge as an interplay between excitatory and inhibitory neurons and underlie cognitive functions and conscious states. These oscillations have distinct expression patterns across cortical layers. Does cellular anatomy enable these oscillations to emerge in specific cortical layers? We present a comprehensive analysis of the laminar distribution of the three main inhibitory cell types in primate cortex (Parvalbumin, Calbindin, and Calretinin positive) and excitatory pyramidal cells. We found a canonical relationship between the laminar anatomy and electrophysiology in 11 distinct primate areas spanning from primary visual to prefrontal cortex. The laminar anatomy explained the expression patterns of neuronal oscillations in different frequencies. Our work provides insight into the cortex-wide cellular mechanisms that generate neuronal oscillations in primates.

Dopamine and beta-band oscillations differentially link to striatal value and motor control.

Parkinson's disease is characterized by decreased dopamine and increased beta-band oscillatory activity accompanying debilitating motor and mood impairments. Coordinate dopamine-beta opposition is considered a normative rule for basal ganglia function. We report a breakdown of this rule. We developed multimodal systems allowing the first simultaneous, chronic recordings of dopamine release and beta-band activity in the striatum of nonhuman primates during behavioral performance. Dopamine and beta signals were anticorrelated over seconds-long time frames, in agreement with the posited rule, but at finer time scales, we identified conditions in which these signals were modulated with the same polarity. These measurements demonstrated that task-elicited beta suppressions preceded dopamine peaks and that relative dopamine-beta timing and polarity depended on reward value, performance history, movement, and striatal domain. These findings establish a new view of coordinate dopamine and beta signaling operations, critical to guide novel strategies for diagnosing and treating Parkinson's disease and related neurodegenerative disorders.

A novel flexible cuff-like microelectrode for dual purpose, acute and chronic electrical interfacing with the mouse cervical vagus nerve.

OBJECTIVE: Neural reflexes regulate immune responses and homeostasis. Advances in bioelectronic medicine indicate that electrical stimulation of the vagus nerve can be used to treat inflammatory disease, yet the understanding of neural signals that regulate inflammation is incomplete. Current interfaces with the vagus nerve do not permit effective chronic stimulation or recording in mouse models, which is vital to studying the molecular and neurophysiological mechanisms that control inflammation homeostasis in health and disease. We developed an implantable, dual purpose, multi-channel, flexible 'microelectrode' array, for recording and stimulation of the mouse vagus nerve. APPROACH: The array was microfabricated on an 8 µm layer of highly biocompatible parylene configured with 16 sites. The microelectrode was evaluated by studying the recording and stimulation performance. Mice were chronically implanted with devices for up to 12 weeks. MAIN RESULTS: Using the microelectrode in vivo, high fidelity signals were recorded during physiological challenges (e.g potassium chloride and interleukin-1ß), and electrical stimulation of the vagus nerve produced the expected significant reduction of blood levels of tumor necrosis factor (TNF) in endotoxemia. Inflammatory cell infiltration at the microelectrode 12 weeks of implantation was limited according to radial distribution analysis of inflammatory cells. SIGNIFICANCE: This novel device provides an important step towards a viable chronic interface for cervical vagus nerve stimulation and recording in mice.

Optimising and communicating options for the control of invasive plant disease when there is epidemiological uncertainty.

Although local eradication is routinely attempted following introduction of disease into a new region, failure is commonplace. Epidemiological principles governing the design of successful control are not well-understood. We analyse factors underlying the effectiveness of reactive eradication of localised outbreaks of invading plant disease, using citrus canker in Florida as a case study, although our results are largely generic, and apply to other plant pathogens (as we show via our second case study, citrus greening). We demonstrate how to optimise control via removal of hosts surrounding detected infection (i.e. localised culling) using a spatially-explicit, stochastic epidemiological model. We show how to define optimal culling strategies that take account of stochasticity in disease spread, and how the effectiveness of disease control depends on epidemiological parameters determining pathogen infectivity, symptom emergence and spread, the initial level of infection, and the logistics and implementation of detection and control. We also consider how optimal culling strategies are conditioned on the levels of risk acceptance/aversion of decision makers, and show how to extend the analyses to account for potential larger-scale impacts of a small-scale outbreak. Control of local outbreaks by culling can be very effective, particularly when started quickly, but the optimum strategy and its performance are strongly dependent on epidemiological parameters (particularly those controlling dispersal and the extent of any cryptic infection, i.e. infectious hosts prior to symptoms), the logistics of detection and control, and the level of local and global risk that is deemed to be acceptable. A version of the model we developed to illustrate our methodology and results to an audience of stakeholders, including policy makers, regulators and growers, is available online as an interactive, user-friendly interface at http://www.webidemics.com/. This version of our model allows the complex epidemiological principles that underlie our results to be communicated to a non-specialist audience.

Cost-effective control of plant disease when epidemiological knowledge is incomplete: modelling Bahia bark scaling of citrus.

A spatially-explicit, stochastic model is developed for Bahia bark scaling, a threat to citrus production in north-eastern Brazil, and is used to assess epidemiological principles underlying the cost-effectiveness of disease control strategies. The model is fitted via Markov chain Monte Carlo with data augmentation to snapshots of disease spread derived from a previously-reported multi-year experiment. Goodness-of-fit tests strongly supported the fit of the model, even though the detailed etiology of the disease is unknown and was not explicitly included in the model. Key epidemiological parameters including the infection rate, incubation period and scale of dispersal are estimated from the spread data. This allows us to scale-up the experimental results to predict the effect of the level of initial inoculum on disease progression in a typically-sized citrus grove. The efficacies of two cultural control measures are assessed: altering the spacing of host plants, and roguing symptomatic trees. Reducing planting density can slow disease spread significantly if the distance between hosts is sufficiently large. However, low density groves have fewer plants per hectare. The optimum density of productive plants is therefore recovered at an intermediate host spacing. Roguing, even when detection of symptomatic plants is imperfect, can lead to very effective control. However, scouting for disease symptoms incurs a cost. We use the model to balance the cost of scouting against the number of plants lost to disease, and show how to determine a roguing schedule that optimises profit. The trade-offs underlying the two optima we identify-the optimal host spacing and the optimal roguing schedule-are applicable to many pathosystems. Our work demonstrates how a carefully parameterised mathematical model can be used to find these optima. It also illustrates how mathematical models can be used in even this most challenging of situations in which the underlying epidemiology is ill-understood.

Coronary fistula of right coronary artery to vena cava superior and ectasia of pulmonary artery.

We report on a patient with coronary heart disease, a coronary fistula of right coronary artery to vena cava superior and pulmonary hypertension. Combined with coronary artery revascularization, the coronary fistula was closed successfully.

Continuous assessment of right ventricular ejection fraction: new pulmonary artery catheter versus transoesophageal echocardiography.

In 25 cardiac surgical patients, right ventricular ejection fraction was continuously measured with a new pulmonary artery catheter and transoesophageal echocardiography, scanning the 'fractional area change' in a standardised transatrial cross section area. Measurements were recorded at three predefined time points (pre-, intra-, and postoperatively). Both methods were compared using the Bland-Altman analysis. Comparing right ventricular ejection fraction values obtained from the pulmonary artery catheter with those assessed by transoesophageal echocardiography, bias was -3.7%, with a precision of 30.9%. Bias and precision significantly improved when the heart rate was less than 100 beats.min(-1), pulmonary artery pressures were low and cardiac performance adequate. In conclusion, the new continuous pulmonary artery catheter system appears to be a valid and useful bedside monitoring device in the haemodynamic management of critically ill patients.

Privileged structures: applications in drug discovery.

Over the past 15 years the privileged structure concept has emerged as a fruitful approach to the discovery of novel biologically active molecules. Privileged structures are molecular scaffolds with versatile binding properties, such that a single scaffold is able to provide potent and selective ligands for a range of different biological targets through modification of functional groups. In addition, privileged structures typically exhibit good drug-like properties, which in turn leads to more drug-like compound libraries and leads. The net result is the production of high quality leads that provide a solid foundation for further development. The identification of privileged structures will be discussed, emphasizing the importance of understanding the structure-target relationships that confer "privileged" status. This understanding allows privileged structure based libraries to be targeted at distinct target families (e.g. GPCRs, LGIC, enzymes/kinases). Privileged structures have been successfully exploited across and within different target families and promises to be an effective approach to the discovery and optimization of novel bioactive molecules. The application of the privileged structure approach, both in traditional medicinal chemistry and in the design of focused libraries, will be discussed with the aid of illustrative examples.

Modulation of sensory suppression: implications for receptive field sizes in the human visual cortex.

Neurophysiological studies in monkeys show that when multiple visual stimuli appear simultaneously in the visual field, they are not processed independently, but rather interact in a mutually suppressive way. This suggests that multiple stimuli compete for neural representation. Consistent with this notion, we have previously found in humans that functional magnetic resonance imaging (fMRI) signals in V1 and ventral extrastriate areas V2, V4, and TEO are smaller for simultaneously presented (i.e., competing) stimuli than for the same stimuli presented sequentially (i.e., not competing). Here we report that suppressive interactions between stimuli are also present in dorsal extrastriate areas V3A and MT, and we compare these interactions to those in areas V1 through TEO. To exclude the possibility that the differences in responses to simultaneously and sequentially presented stimuli were due to differences in the number of transient onsets, we tested for suppressive interactions in area V4, in an experiment that held constant the number of transient onsets. We found that the fMRI response to a stimulus in the upper visual field was suppressed by the presence of nearby stimuli in the lower visual field. Further, we excluded the possibility that the greater fMRI responses to sequential compared with simultaneous presentations were due to exogeneous attentional cueing by having our subjects count T's or L's at fixation, an attentionally demanding task. Behavioral testing demonstrated that neither condition interfered with performance of the T/L task. Our previous findings suggested that suppressive interactions among nearby stimuli in areas V1 through TEO were scaled to the receptive field (RF) sizes of neurons in those areas. Here we tested this idea by parametrically varying the spatial separation among stimuli in the display. Display sizes ranged from 2 x 2 degrees to 7 x 7 degrees and were centered at 5.5 degrees eccentricity. Based on the effects of display size on the magnitude of suppressive interactions, we estimated that RF sizes at an eccentricity of 5.5 degrees were <2 degrees in V1, 2-4 degrees in V2, 4-6 degrees in V4, larger than 7 degrees (but still confined to a quadrant) in TEO, and larger than 6 degrees (confined to a quadrant) in V3A. These estimates of RF sizes in human visual cortex are strikingly similar to those measured in physiological mapping studies in the homologous visual areas in monkeys.

Responses of neurons in macaque area V4 during memory-guided visual search.

In a typical scene with many different objects, attentional mechanisms are needed to select relevant objects for visual processing and control over behavior. To test the role of area V4 in the selection of objects based on non-spatial features, we recorded from V4 neurons in the monkey, using a visual search paradigm. A cue stimulus was presented at the center of gaze, followed by a blank delay period. After the delay, a two-stimulus array was presented extrafoveally, and the monkey was rewarded for detecting the target stimulus matching the cue. The array was composed of one 'good' stimulus (effective in driving the cell when presented alone) and one 'poor' stimulus (ineffective in driving the cell when presented alone). When the choice array was presented in the receptive field (RF) of the neuron, many cells showed suppressive interactions between the stimuli as well as strong attention effects. Within 150--200 ms of array onset, responses to the array were determined by the target stimulus. If the target was the good stimulus, the response to the array became equal to the response to the good stimulus presented alone. If the target was the poor stimulus, the response approached the response to that stimulus presented alone. Thus the influence of the nontarget stimulus was filtered out. These effects were reduced or eliminated when the poor stimulus was located outside the RF and, therefore, no longer competing for the cell's response. Overall, the results support a 'biased competition' model of attention, according to which objects in the visual field compete for representation in the cortex, and this competition is biased in favor of the behaviorally relevant object.

Learning increases stimulus salience in anterior inferior temporal cortex of the macaque.

With experience, an object can become behaviorally relevant and thereby quickly attract our interest when presented in a visual scene. A likely site of these learning effects is anterior inferior temporal (aIT) cortex, where neurons are thought to participate in the filtering of irrelevant information out of complex visual displays. We trained monkeys to saccade consistently to one of two pictures in an array, in return for a reward. The array was constructed by pairing two stimuli, one of which elicited a good response from the cell when presented alone ("good" stimulus) and the other of which elicited a poor response ("poor" stimulus). The activity of aIT cells was recorded while monkeys learned to saccade to either the good or poor stimulus in the array. We found that neuronal responses to the array were greater (before the saccade occurred) when training reinforced a saccade to the good stimulus than when training reinforced a saccade to the poor stimulus. This difference was not present on incorrect trials, i.e., when saccades to the incorrect stimulus were made. Thus the difference in activity was correlated with performance. The response difference grew over the course of the recording session, in parallel with the improvement in performance. The response difference was not preceded by a difference in the baseline activity of the cells, unlike what was found in studies of cued visual search and working memory in aIT cortex. Furthermore, we found similar effects in a version of the task in which any of 10 possible pairs of stimuli, prelearned before the recording session, could appear on a given trial, thereby precluding a working memory strategy. The results suggest that increasing the behavioral significance of a stimulus through training alters the neural representation of that stimulus in aIT cortex. As a result, neurons responding to features of the relevant stimulus may suppress neurons responding to features of irrelevant stimuli.

Contextual modulation in primary visual cortex of macaques.

Recent studies have suggested that V1 neurons extract figures from their backgrounds, in that they respond better to interior features of figures than to equivalent features of background stimuli. This is reportedly true even when the figure boundaries are distant from the borders of the classical receptive field (RF). To test the role of V1 neurons in figure-ground segregation, we recorded their responses to texture figures on texture backgrounds, centered on the RF. The texture elements of the figures remained identical across trials, and figure boundaries were defined by orientation differences between the elements in the background texture relative to elements in the figure. For nearly all neurons (98/102), responses to a large texture figure did not differ from the responses to a uniform-texture background. Although many neurons gave enhanced responses to texture boundaries, this occurred only when the boundaries were within or close to the RF borders. Similar effects were found in V2. For neurons in V1, the limited spatial extent of the contextual modulation was not increased either at low stimulus contrast or when the animal was rewarded for detecting an orientation-defined figure. Thus, V1 neurons appear to signal texture boundaries rather than figures per se. Unexpectedly, many V1 neurons gave significant long-latency responses to texture stimuli located entirely outside the classical RF, up to 5 degrees from the RF border in some cases. However, these responses did not depend on the stimulus forming a figure that contained the RF. Although V1 neurons are influenced by stimuli outside the classical RF, they do not appear to segregate figures from ground.

Modulation of oscillatory neuronal synchronization by selective visual attention.

In crowded visual scenes, attention is needed to select relevant stimuli. To study the underlying mechanisms, we recorded neurons in cortical area V4 while macaque monkeys attended to behaviorally relevant stimuli and ignored distracters. Neurons activated by the attended stimulus showed increased gamma-frequency (35 to 90 hertz) synchronization but reduced low-frequency (<17 hertz) synchronization compared with neurons at nearby V4 sites activated by distracters. Because postsynaptic integration times are short, these localized changes in synchronization may serve to amplify behaviorally relevant signals in the cortex.

New syntheses of the C,D-ring pyrromethenones of phytochrome and phycocyanin.

Pyrromethenone 7, the C,D-ring segment of phytochrome (Pr, 4), has been prepared in an efficient fashion employing three new strategies. Each of these has potential advantages for the synthesis of labeled material. Our first approach is related to the Gossauer synthesis, with the difference that strong alkali is avoided in the condensation of the C- and D-ring components 8 and 17. The key silyloxypyrrole 17 was readily prepared on multigram scales beginning with inexpensive butyrolactone (10). A second synthesis began with 2-acetylbutyrolactone (41). The key steps involved conversion of 41 to the Z-enoltriflate 42, followed by Pd(0)-catalyzed coupling with trimethylsilylacetylene, p-chlorophenylselenide ring opening, and finally, amidation to afford the ring-D synthon 45 having the proper geometry and oxidation state for conversion to 7. Sonogashira coupling of 45 with the iodopyrrole 22, followed by oxidative elimination, and F(-)-induced 5-exo-dig cyclization of the resultant pyrroloalkyne 47, then completed the synthesis. In similar fashion, we have also prepared pyrromethenone 6, the C,D-ring segment of phycocyanin (2).

Clustering of perirhinal neurons with similar properties following visual experience in adult monkeys.

The functional organization of early visual areas seems to be largely determined during development. However, the organization of areas important for learning and memory, such as perirhinal cortex, may be modifiable in adults. To test this hypothesis, we recorded from pairs of neurons in perirhinal cortex of macaques while they viewed multiple complex stimuli. For novel stimuli, neuronal response preferences for pairs of nearby neurons and far-apart neurons were uncorrelated. However, after one day of experience with the stimuli, response preferences of nearby neurons became more similar. We conclude that specific visual experience induces development of clusters of perirhinal neurons with similar stimulus preferences.

Attention increases sensitivity of V4 neurons.

When attention is directed to a location in the visual field, sensitivity to stimuli at that location is increased. At the neuronal level, this could arise either through a multiplicative increase in firing rate or through an increase in the effective strength of the stimulus. To test conflicting predictions of these alternative models, we recorded responses of V4 neurons to stimuli across a range of luminance contrasts and measured the change in response when monkeys attended to them in order to discriminate a target stimulus from nontargets. Attention caused greater increases in response at low contrast than at high contrast, consistent with an increase in effective stimulus strength. On average, attention increased the effective contrast of the attended stimulus by a factor of 1.51, an increase of 51% of its physical contrast.

[Volumetric analysis and visualization of cardiologic ultrasound data]. / Volumetrische Analyse und Visualisierung kardiologischer Ultraschalldaten.

BACKGROUND: Echocardiography is a standard imaging technique for the assessment of heart valve disease. The good spatial and temporal resolution is the basis for different methods which provide information about the severity of such defects. Dynamic colour visualisation and volumetric measurements of regurgitant jets are a new evaluating tool for the assessment of heart valve insufficiencies. METHODS: The regurgitant jet volume of 58 patients was evaluated on an external work-station after segmentation of the left atrium and compared to regurgitant volume; the correlation was good. This result is valid for central jets as well as for eccentric jets. CONCLUSIONS: Measurement of regurgitant jet volume is a method which considers the three-dimensional shape of the examined volume. Real-time visualisation techniques which support the interactive clipping of morphological structures provide dynamic visualisation of intracardiac flow during the heart cycle. Dynamic colour visualisation of jets together with myocardial structures allows the assignment of intracardiac flow to morphological structures.

Substituted 3-(2-benzoxazyl)-benzimidazol-2-(1H)-ones: a new class of GABA(A) brain receptor ligands.

A novel class of potent benzodiazepine receptor (BZR) ligands has been designed and synthesized aided by molecular modeling of known benzodiazepine ligands such as CGS-8216 and the use of known pharmacophore models.