Cholinergic Behavior State-Dependent Mechanisms of Neocortical Gain Control: a Neurocomputational Study.

The embodied mammalian brain evolved to adapt to an only partially known and knowable world. The adaptive labeling of the world is critically dependent on the neocortex which in turn is modulated by a range of subcortical systems such as the thalamus, ventral striatum, and the amygdala. A particular case in point is the learning paradigm of classical conditioning where acquired representations of states of the world such as sounds and visual features are associated with predefined discrete behavioral responses such as eye blinks and freezing. Learning progresses in a very specific order, where the animal first identifies the features of the task that are predictive of a motivational state and then forms the association of the current sensory state with a particular action and shapes this action to the specific contingency. This adaptive feature selection has both attentional and memory components, i.e., a behaviorally relevant state must be detected while its representation must be stabilized to allow its interfacing to output systems. Here, we present a computational model of the neocortical systems that underlie this feature detection process and its state-dependent modulation mediated by the amygdala and its downstream target the nucleus basalis of Meynert. In particular, we analyze the role of different populations of inhibitory interneurons in the regulation of cortical activity and their state-dependent gating of sensory signals. In our model, we show that the neuromodulator acetylcholine (ACh), which is in turn under control of the amygdala, plays a distinct role in the dynamics of each population and their associated gating function serving the detection of novel sensory features not captured in the state of the network, facilitating the adjustment of cortical sensory representations and regulating the switching between modes of attention and learning.

Airway segmentation and analysis for the study of mouse models of lung disease using micro-CT.

Animal models of lung disease are gaining importance in understanding the underlying mechanisms of diseases such as emphysema and lung cancer. Micro-CT allows in vivo imaging of these models, thus permitting the study of the progression of the disease or the effect of therapeutic drugs in longitudinal studies. Automated analysis of micro-CT images can be helpful to understand the physiology of diseased lungs, especially when combined with measurements of respiratory system input impedance. In this work, we present a fast and robust murine airway segmentation and reconstruction algorithm. The algorithm is based on a propagating fast marching wavefront that, as it grows, divides the tree into segments. We devised a number of specific rules to guarantee that the front propagates only inside the airways and to avoid leaking into the parenchyma. The algorithm was tested on normal mice, a mouse model of chronic inflammation and a mouse model of emphysema. A comparison with manual segmentations of two independent observers shows that the specificity and sensitivity values of our method are comparable to the inter-observer variability, and radius measurements of the mainstem bronchi reveal significant differences between healthy and diseased mice. Combining measurements of the automatically segmented airways with the parameters of the constant phase model provides extra information on how disease affects lung function.

Utility of biochemical markers in the follow-up of heart transplant recipients.

Endomyocardial biopsy (EMB) is currently the standard method to diagnose acute graft rejection. However, considering the potential complications of this procedure, a noninvasive marker of rejection would be an ideal alternative or at least a helpful adjunct to posttransplant management. We measured myoglobin (Myo), creatine kinase MB mass (CK-MBm), troponin T (cTnT), serum amyloid A (SAA), and C-reactive protein (CRP) in 57 patients (mean age 37.5 years) who underwent orthotopic heart transplantation for end-stage cardiac failure between January and December 2001.Endomyocardial biopsies were performed routinely after surgery and histologically diagnosed rejection was graded according to the criteria of the International Society of Heart and Lung Transplantation. Concomittant with the biopsies, blood samples were drawn from the coronary sinus (central blood samples) and from a peripheral vein (peripheral blood samples) to assay biochemical markers. Among 149 EMB evaluated, 87 were negative (grade 0); 28 showed grade 1a rejection; 26 showed grade 1b; and 8 showed grade > 1b (2 were grade 2, 6 were grade 3a). Grades 0 and 1a were considered to be negative, while grades 1b and >1b were considered positive indicating potential acute graft rejection. cTnT, Myo, CK-MBm, SAA, and CRP levels were measured in 149 central blood samples and 149 peripheral blood samples. Myo and CK-MBm did not show significant changes. cTnT seems to be a potentially useful addition to the EMB results, while SAA and CRP showed variations with respect to EMB grade both in central and peripheral samples.

Left atrial function: bridge to central and hormonal determinants of exercise capacity in patients with chronic heart failure.

UNLABELLED: The stroke volume response to exercise is a critical determinant in meeting peripheral metabolic demands in patients with chronic hear failure. The Left atrium, by its position, is important in coupling right and left ventricles, to left preload reserve and to modulate sympathetic activity. We performed this study to investigate the relationship between exercise capacity and diastolic and systolic left atrium function in patients with chronic heart failure. METHODS: We considered 128 consecutive patients with severe chronic heart failure (EF < 35%) due to ischemic or idiopathic dilated cardiomyopathy. Cardiac output, right atrial pressure, pulmonary artery pressures and mean pulmonary wedge pressure (A, X, V, Y wedge pressures) were determined during right cardiac catheterization. By Echocardiography evaluation, we measured atrial pressures and volume during early and late left atrial systolic filling and we calculated left atrial chamber stiffness by this equation P = A*eKV1. (P = left atrial pressure; A = elastic constant (mmHg*ml); e = the base of the natural logarithm; V1 = left atrial volume (ml); K = left atrial chamber stiffness constant (ml-1) = ln (V/X)/(maximal--minimal left atrial volumes)). All patients performed cardiopulmonary exercise test with modified Noughton protocol. Plasma norepinephrine and Atrial natriuretic factor levels were determined. RESULTS: Maximal and minimal left atrial volumes were inversely related to oxygen consumption (r = -.44, p < .001; r = -.61, p < .001). At rest, no differences were found in plasma norepinephrine concentrations (309 +/- 152 pg/ml vs 309 +/- 394 pg/ml; p = ns) and systemic vascular resistance (1706 +/- 435 vs 1771 +/- 524 dynes/cm sec-5; p = ns) in patients with large or normal left atrial volumes. During exercise the chronotropic response increased less in patients with large atrial volumes (56 +/- 13 vs 45 +/- 14; p = .001). The left atrial chamber stiffness constant was inversely related to peak oxygen consumption and exercise time. Patients with different chamber stiffness showed statistical difference in peak VO2 (16 +/- 4 vs 11 +/- 3 ml/kg/min; p = .0001). Left atrial ejection fraction was directly related to peak oxygen consumption (r = 0.55), but the most strongly correlation was with atrial filling fraction (r = .67). CONCLUSIONS: This study demonstrates a strong relationship between left atrial function and exercise capacity in patients with chronic heart failure.