Switching Operation Modes in the Neocortex via Cholinergic Neuromodulation : A Computational Model of Uncertainty, Learning, and Inhibition.

In order to deal with the uncertainty in the world, our brains need to be able to flexibly switch between the exploration of new sensory representations and exploitation of previously acquired ones. This requires forming accurate estimations of what and how much something is expected. While modeling has allowed for the development of several ways to form predictions, how the brain could implement those is still under debate. Here, we recognize acetylcholine as one of the main neuromodulators driving learning based on uncertainty, promoting the exploration of new sensory representations. We identify its interactions with cortical inhibitory interneurons and derive a biophysically grounded computational model able to capture and learn from uncertainty. This model allows us to understand inhibition beyond gain control by suggesting that different interneuron subtypes either encode predictions or estimate their uncertainty, facilitating detection of unexpected cues. Moreover, we show how acetylcholine-like neuromodulation uniquely interacts with global and local sources of inhibition, disrupting perceptual certainty and promoting the rapid acquisition of new perceptual cues. Altogether, our model proposes that cortical acetylcholine favors sensory exploration over exploitation in a cortical microcircuit dedicated to estimating sensory uncertainty.

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.

Correlaciones anatomoclínicas en la enfermedad de chagas / Correlation anatomoclínical in the chagas disease

La Miocardiopatía Chagásica Crónica constituye la forma de miocardiopatía dilatada más frecuentemente encontrada en este trabajo el cual se basa en un material de 14.872 necropsias realizadas durante un período de más de 40 años. En las etapas precoces de la fase indeterminada el corazón chagásico puede encontrarse macroscópicamente normal, como es el caso de pacientes fallecidos súbitamente. Luego cabe observar tres tipos de remodelación ventricular en la fase crónica (concéntrica, ambigua y excéntrica) las cuales suministran la base patológica para explicar la secuencia de las manifestaciones clínicas observadas en la fase crónica

Sustained ventricular tachycardia in chronic chagasic myocarditis: electrophysiologic and pharmacologic characteristics.

Sustained ventricular tachycardia (VT) develops in many patients with chronic Chagasic myocarditis. Programmed stimulation was used to study the electrophysiologic characteristics of VT in 15 patients with Chagas' cardiomyopathy. Nine patients were in New York Heart Association functional class I, 5 were in class II and 1 patient was in class III. The average ejection fraction was 56 +/- 7%, which is somewhat better than that reported in patients with VT owing to idiopathic cardiomyopathy. In 11 patients VT could be reproducibly initiated and terminated by programmed stimulation. Intravenous mexilitene prevented induction of VT in 7 of 8 patients; amiodarone did not prevent induction in 3 of 4 patients. Our data indicate that the mechanism of VT is likely to be reentrant in many patients, and therefore VT can be produced by extrastimuli. Electrophysiologic study is therefore useful for establishing the diagnosis of sustained VT and may be useful for guiding initial therapy in selected cases of Chagas' disease.

Echocardiographic features of impaired left ventricular diastolic function in Chagas's heart disease.

To study left ventricular diastolic function in Chagas's disease, simultaneous echocardiograms, phonocardiograms, and apexcardiograms were recorded in 20 asymptomatic patients with positive Chagas's serology and no signs of heart disease (group 1), 12 with Chagas's heart disease and symptoms of ventricular arrhythmia but no heart failure (group 2), 20 normal subjects (group 3), and 12 patients with left ventricular hypertrophy (group 4). The recordings were digitised to determine left ventricular isovolumic relaxation time and the rate and duration of left ventricular cavity dimension increase and wall thinning. In groups 1 and 2 (a) aortic valve closure (A2) and mitral valve opening were significantly delayed relative to minimum dimension and were associated with prolonged isovolumic relaxation, (b) left ventricular cavity size was abnormally increased during isovolumic relaxation and abnormally reduced during isovolumic contraction, and (c) peak rate of posterior wall thinning and dimension increase were significantly reduced and duration of posterior wall thinning was significantly prolonged; both of these abnormalities occurred at the onset of diastolic filling. These abnormalities were more pronounced in group 2 and were accompanied by an increase in the height of the apexcardiogram "a" wave, an indication of pronounced atrial systole secondary to end diastolic filling impairment due to reduced left ventricular distensibility. Group 4, which had an established pattern of diastolic abnormalities, showed changes similar to those in group 2; however, the delay in aortic valve closure (A2) and in mitral valve opening and the degree of dimension change were greater in the latter group. Thus early isovolumic relaxation and left ventricular abnormalities were pronounced in the patients with Chagas's heart disease and may precede systolic compromise, which may become apparent in later stages of the disease. The digitised method is valuable in the early detection of myocardial damage.

Radionuclide evaluation of left-ventricular function in chronic Chagas' cardiomyopathy.

Left-ventricular ejection fraction (LVEF) and abnormalities of regional wall motion (WMA) were studied by means of radionuclide ventriculography in 41 patients prospectively diagnosed as having chronic Chagas' disease. Thirteen patients were asymptomatic (ASY), 16 were arrhythmic (ARR), and 12 had congestive heart failure (CHF). Mean LVEF was normal in ASY (0.64 +/- 0.06) but markedly depressed in CHF (0.28 +/- 0.08). Regional WMAs were minimal in ASY and their severity increased in ARR. Most CHFs (75%) had diffuse hypokinesia of the left ventricle. The region most frequently affected was the infero-apical (63%). Seven patients had a distinct apical aneurysm. Correlation between radionuclide and contrast ventriculography data was good in 17 patients. For LVEF, r = 0.90. For WMA there was agreement between the two techniques in 77% of 65 segments compared. Best agreement occurred with infero-apical lesions (88%), and worst with septal (69%). Selective coronary arteriography showed normal arteries in all patients. Therefore, chronic Chagas' heart disease joins ischemic heart disease as a cause of regional WMA.

Value of two-dimensional echocardiography in endomyocardial disease with and without eosinophilia. A clinical and pathologic study.

Ten patients (six women and four men) with endomyocardial disease, four with and six without hypereosinophilia, were studied by two-dimensional echocardiography (2-D echo). Eight had biventricular congestive heart failure and two had atypical chest pain with ischemic electrocardiographic changes. The patients were 15-50 years old (mean 40 years) and duration of illness was 2-9 years (mean 4.4 years). Nine had cardiac catheterization and three pathologic examination. Characteristic 2-D echo findings included apical obliteration of one or both ventricles by echogenic material suggestive of fibrosis or thrombosis; bright, specular echoes at the cavity surface of the apical obliteration suggesting patchy calcification; preserved left apical systolic inward motion, which differed significantly from the dyskinetic motion of thrombotic apical obliteration of ischemic or Chagasic origin (p less than 0.001); involvement of the papillary muscles and posterior atrioventricular valve; preserved ventricular contractile function in most patients; and the combination of normal-to-small ventricles with large atria. None of 14 subjects with secondary hypereosinophilia followed for 15.4 months developed similar 2-D echo findings. We conclude that both forms of endomyocardial disease had a 2-D echo pattern useful for noninvasive recognition and differentiation from patients who have valvular heart disease, constrictive pericarditis and cardiomyopathies of other origins.

Endomyocardial disease in South America--report on 23 cases in Venezuela.

Twenty-three cases of endomyocardial disease (ED) are presented, studied in Venezuela, a tropical country in northern South America. The diagnosis was confirmed in 18 cases by means of pathological studies, and in 5 cases by angiocardiography which showed the characteristic obliterative ventricular lesions. Eosinophilia was present in 35% of the patients. The most frequent clinical feature was heart failure associated with mitral regurgitation. Systemic embolism was the first clinical feature in 5 cases. In 2 cases, ED was associated with autoimmune haemolytic anaemia or vasculitis. Necropsy revealed a predominance of the left-sided (9/16 cases) and biventricular (6/16 cases) types. The pathological lesions were characterised by fibrous thickening of the endocardium at the apex and the ventricular inflow tracts extending to the myocardium and involving the atrioventricular valves. ED is frequently misdiagnosed as rheumatic valvular cardiopathy. The two-dimensional echocardiogram is a very useful procedure for determining the spatial anatomy of ED. The echo findings were closely correlated with ventriculographic and necropsy findings. Even though ED is widely spread around the world, it is most frequently found in tropical and subtropical countries in Africa, Asia and America, such as Venezuela and Brazil. This suggests that there are aetiological factors in these latitudes, about which little is known.

Diagnosis of Chagas' cardiomyopathy. Non-invasive techniques.

The natural history of Chagas' disease and its manifestations when the heart is involved are detailed clinically and pathologically. Three phases are recognized: the acute phase, lasting from 1-3 months, the latent phase, which may last from 10-20 years, and the chronic phase, which has the most serious manifestations. This phase is subdivided into three clinical stages. An analysis of the varied cardiac manifestations on 235 patients is included.

Cuatro años de estudio longitudinal de una comunidad rural con endemicidad chagásica / A 4-year follow-up study of a rural community with endemic chagas'disease

The four-year follow-up study reported herein represents the continuation of a previous cross-sectional study carried out in a rural community (Belen, Venezuela). The earlier study included 1,210 persons out of a total of 1,656 inhabitants, all over five years of age, and demonstrated a high prevalence of Chagas' infection (47.3 per cent) and a high rate of Chagas' disease seropositivity among those with chronic myocardial heart disease (84.8 per cent); heart disease was found in 17.3 per cent of persons studied. It included clinical, electrocardiographic and radiological analyses

The present report describes the results of the four-year follow-up study performed in 812 persons, which permitted to establish the incidence of Chagas' infection (16.3 per cent) and that of chagasic heart disease (2.2 per cent) in four years. The report also included the clinical, electrocardiographic and radiological analyses of cases with previous heart disease as well as new cases. Different evolutive electrocardiographic patterns have been found, including serial electrocardiographic variations ranging from normal to definitely abnormal. The mortality occurred in the sample during the observation period is reported(AU)

A 4-year follow-up study of a rural community with endemic Chagas' disease.

The paper reports on a 4-year follow-up study that represents the continuation of a previous cross-sectional study on Chagas' disease carried out in a rural community (Belén) in Venezuela. The earlier study included 1210 persons all over 5 years of age out of a total of 1656 inhabitants and demonstrated a high prevalence of Chagas' infection (47.3%) and a high rate of Chagas' disease seropositivity among those with chronic myocardial heart disease (84.8%); heart disease was found in 17.3% of persons studied. The follow-up study was based on 812 persons and established that in the sample the frequency of Chagas' infection was 16.3% and that of heart disease 2.2%. Clinical, electrocardiographic and radiological analyses were made on patients with previous heart disease as well as on new patients. Different evolutive electrocardiographic patterns have been found, including variations ranging from normal to definitively abnormal.