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Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions.

The prefrontal cortex guides behaviors, thoughts, and feelings using representational knowledge, i.e., working memory. These fundamental cognitive abilities subserve the so-called executive functions: the ability to inhibit inappropriate behaviors and thoughts, regulate our attention, monitor our actions, and plan and organize for the future. Neuropsychological and imaging studies indicate that these prefrontal cortex functions are weaker in patients with attention-deficit/hyperactivity disorder and contribute substantially to attention-deficit/hyperactivity disorder symptomology. Research in animals indicates that the prefrontal cortex is very sensitive to its neurochemical environment and that small changes in catecholamine modulation of prefrontal cortex cells can have profound effects on the ability of the prefrontal cortex to guide behavior. Optimal levels of norepinephrine acting at postsynaptic alpha-2A-adrenoceptors and dopamine acting at D1 receptors are essential to prefrontal cortex function. Blockade of norepinephrine alpha-2-adrenoceptors in prefrontal cortex markedly impairs prefrontal cortex function and mimics most of the symptoms of attention-deficit/hyperactivity disorder, including impulsivity and locomotor hyperactivity. Conversely, stimulation of alpha-2-adrenoceptors in prefrontal cortex strengthens prefrontal cortex regulation of behavior and reduces distractibility. Most effective treatments for attention-deficit/hyperactivity disorder facilitate catecholamine transmission and likely have their therapeutic actions by optimizing catecholamine actions in prefrontal cortex.

Adamantane↗

Assessing cortical functional connectivity by linear inverse estimation and directed transfer function: simulations and application to real data.

OBJECTIVE: To test a technique called Directed Transfer Function (DTF) for the estimation of human cortical connectivity, by means of simulation study and human study, using high resolution EEG recordings related to finger movements. METHODS: The method of the Directed Transfer Function (DTF) is a frequency-domain approach, based on a multivariate autoregressive modeling of time series and on the concept of Granger causality. Since the spreading of the potential from the cortex to the sensors makes it difficult to infer the relation between the spatial patterns on the sensor space and those on the cortical sites, we propose the use of the DTF method on cortical signals estimated from high resolution EEG recordings, which exhibit a higher spatial resolution than conventional cerebral electromagnetic measures. The simulation study was followed by an analysis of variance (ANOVA) of the results obtained for different levels of Signal to Noise Ratio (SNR) and temporal length, as they have been systematically imposed on simulated signals. The whole methodology was then applied to high resolution EEG data recorded during a visually paced finger movement. RESULTS: The statistical analysis performed returns that during simulations, DTF is able to estimate correctly the imposed connectivity patterns under reasonable operative conditions, i.e. when data exhibit a SNR of at least 3 and a length of at least 75 s of non-consecutive recordings at 64 Hz of sampling rate, equivalent, more generally, to 4800 data samples. CONCLUSIONS: Functional connectivity patterns of cortical activity can be effectively estimated under general conditions met in any practical EEG recordings, by combining high resolution EEG techniques, linear inverse estimation and the DTF method. SIGNIFICANCE: The estimation of cortical connectivity can be performed not only with hemodynamic measurements, by using functional MRI recordings, but also with modern EEG recordings treated with advanced computational techniques.

Analysis of Variance↗

Functional explanation and the function of explanation.

Teleological explanations (TEs) account for the existence or properties of an entity in terms of a function: we have hearts because they pump blood, and telephones for communication. While many teleological explanations seem appropriate, others are clearly not warranted--for example, that rain exists for plants to grow. Five experiments explore the theoretical commitments that underlie teleological explanations. With the analysis of [Wright, L. (1976). Teleological Explanations. Berkeley, CA: University of California Press] from philosophy as a point of departure, we examine in Experiment 1 whether teleological explanations are interpreted causally, and confirm that TEs are only accepted when the function invoked in the explanation played a causal role in bringing about what is being explained. However, we also find that playing a causal role is not sufficient for all participants to accept TEs. Experiment 2 shows that this is not because participants fail to appreciate the causal structure of the scenarios used as stimuli. In Experiments 3-5 we show that the additional requirement for TE acceptance is that the process by which the function played a causal role must be general in the sense of conforming to a predictable pattern. These findings motivate a proposal, Explanation for Export, which suggests that a psychological function of explanation is to highlight information likely to subserve future prediction and intervention. We relate our proposal to normative accounts of explanation from philosophy of science, as well as to claims from psychology and artificial intelligence.

Adult↗

Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC).

AIM: The purpose of this study was to investigate the effects of carvedilol on diastolic function (DF) in heart failure patients with preserved left ventricular (LV) systolic function and abnormal DF. PATIENTS AND METHODS: We randomised 113 patients with diastolic heart failure (DHF) (symptomatic, with normal systolic LV function and abnormal DF) into a double blind multi-centre study. The patients received either carvedilol or matching placebo in addition to conventional treatment. After uptitration, treatment was continued for 6 months. Two-dimensional and Doppler echocardiography were used for quantification of LV function at baseline and at follow-up. Four different DF variables were evaluated by Doppler echocardiography: mitral flow E:A ratio, deceleration time (DT), isovolumic relaxation time (IVRT) and the ratio of systolic/diastolic pulmonary venous flow velocity (pv-S/D). Primary endpoint was change in the integrated quantitative assessment of all four variables during the study. RESULTS: Ninety-seven patients completed the study. A mitral flow pattern reflecting a relaxation abnormality was recorded in 95 patients. There was no effect on the primary endpoint, although a trend towards a better effect in carvedilol treated patients was noticed in patients with heart rates above 71 beats per minute. At the end of the study, there was a statistically significant improvement in E:A ratio in patients treated with carvedilol (0.72 to 0.83) vs. placebo (0.71 to 0.76), P<0.05. CONCLUSIONS: Treatment with carvedilol resulted in a significant improvement in E:A ratio in patients with heart failure due to a LV relaxation abnormality. E:A ratio was found to be the most useful variable to identify diastolic dysfunction in this patient population. This effect was observed particularly in patients with higher heart rates at baseline.

Adrenergic beta-Antagonists↗

Divergent PXR function in seals: Endocrine adaptation or functional loss?

Seals accumulate xenobiotics through dietary biomagnification and exposure to polluted marine environments, with contaminants concentrating in their blubber. Biotransformation mitigates xenobiotic toxicity by converting lipophilic compounds into excretable hydrophilic metabolites, a process coordinated by nuclear receptors including the Pregnane X Receptor (PXR), whose plastic ligand-binding domain enables broad xenobiotic sensing. By examining PXR in pinnipeds, we investigated the evolutionary conservation and functional characterization of PXR using genomic sequence analysis, protein structural prediction, and transactivation assays, revealing broadly conserved structural features alongside species-specific functional divergence in receptor responsiveness to environmental stressors. Specifically, the obtained results highlight divergent gene and functional landscapes with ORF-disrupting mutations identified in Monachus monachus and Neomonachus schauinslandi that abolish receptor activation toward known PXR ligands. In contrast, Leptonychotes weddelli retained an intact PXR ORF but showed reduced receptor activity, revealing functional divergence in PXR among pinnipeds.

Biotransformation↗

Detection of abnormal left ventricular function by Doppler tissue imaging in patients with a first myocardial infarction and showing normal function assessed by conventional echocardiography.

AIMS: The aim of the study was to characterize left ventricular (LV) function by Doppler tissue imaging (DTI) after a first myocardial infarction (MI) where the conventional echo-Doppler parameters showed no abnormalities. METHODS: Out of 202 patients who were referred for an echocardiogram, 19 patients were previously healthy and had a normal ejection fraction and no wall motion abnormalities at echocardiogram. These 19 patients were compared with 16 age-matched healthy subjects (HS). The longitudinal LV function was assessed using the mitral annular velocities (mean value from four different sites of the LV) determined by DTI. RESULTS: The patients with MI had significantly reduced peak systolic and peak early diastolic mitral annular velocities compared to HS (8.6 v. 9.7 cm/s, P<0.001 for systolic velocity, and 10.9 v. 12.3 cm/s, P<0.01 for diastolic velocity, respectively). The patients had normal diastolic LV function assessed by the conventional Doppler echocardiogram (e.g. transmitral flow, IVRT and pulmonary venous flow patterns). To assess the LV filling pressure, the ratio of the transmitral early wave velocity assessed by conventional echo-Doppler and peak early diastolic mitral annular velocity determined by DTI (E/Edti) was used. The E/Edti was significantly higher in patients than in HS (7.0 v. 5.7, P<0.05). CONCLUSION: Previously healthy subjects who are suffering from a first MI and showing normal systolic and diastolic LV function, determined by conventional echo-Doppler methods, show decreased mitral annular systolic and diastolic velocities determined by DTI compared to healthy subjects. This is probably evidence of mild subendocardial damage due to MI that remains undetected by conventional echo-Doppler methods.

Acute Disease↗

Effect of preoperative tear function on early functional visual acuity after laser in situ keratomileusis.

PURPOSE: To assess the effect of preoperative tear function on early changes in functional visual acuity (FVA) after laser in situ keratomileusis (LASIK). SETTING: Minamiaoyama Eye Clinic, Tokyo, Japan. METHODS: This prospective single-center study assessed the effect of preoperative and postoperative tear functions on FVA in 30 eyes of 15 patients who had LASIK. Functional visual acuity was defined as the binocular recognition acuity measured by the FVA tester (Wellsystem) during a 10-second, blink-free period. All patients had a Schirmer test with anesthesia and tear-film breakup time (BUT) measurements preoperatively and 1 day and 1 week after LASIK. Corneal topography and Landolt visual acuity and FVA measurements were performed before surgery and 1 day and 1 week after LASIK. Eyes with a Schirmer test reading less than 5.0 mm and a BUT less than 5 seconds were grouped as definite dry eye (DDE). Eyes with a normal Schirmer test score but a shortened BUT were grouped as probable dry eye (PDE). RESULTS: In all patients, the best uncorrected Landolt visual acuity was 20/20 or better at the postoperative examination times. In the DDE group, the mean preoperative FVA declined from 1.2 to 0.75 +/- 0.16 (SD) at 1 day and increased to 1.2 at 1 week. No change in FVA was observed postoperatively in the PDE group. CONCLUSION: Laser in situ keratomileusis patients with low basal tearing and full uncorrected distance Landolt acuity may experience a transient decrease in FVA that returns to baseline within 1 week.

Adult↗

On the international stability of health care expenditure functions: are government and private functions similar?

This paper studies the stability of health care expenditure functions in a sample of OECD countries. We adopt the cointegration approach and the results show that there is a long-term relationship between total health care expenditure (HCE) and gross domestic product (GDP). However, the existence of cointegration is only shown when we admit the presence of some changes in the elasticities of the model. Our results also provide evidence against the existence of a unique relationship between health and GDP for the sample. Thus, we can conclude that the differences in health systems may cause differences in the aggregate functions. Additionally, we examine aggregate health functions for government (GHCE) and private expenditures (PHCE), again finding evidence of different patterns of behaviour. Finally, we open a discussion on the character of health as a necessary or luxury good. In this context, we find differences between the government and the private function. In order to illustrate these findings, we propose a theoretical model as an example of the influence of political decisions on income elasticity.

Global Health↗

Biomechanical assessments of lumbar spinal function. How low back pain sufferers differ from normals. Implications for outcome measures research. Part I: kinematic assessments of lumbar function.

OBJECTIVE: To review new and advanced biomechanical assessment techniques for the lumbar spine and illustrate the differences in lumbar function in patients with low back pain and asymtomatic subjects. DATA SOURCES: The biomedical literature was searched for research and reviews on spinal kinematic differences between low back pain subjects and healthy controls. A data search for articles indexed on MEDLINE until April 2002 was performed. RESULTS: Kinematic measurements of lumbar function were categorized into 3 areas where low back patients may differ from normals: (1) end range of motion during simple movements; (2) higher order kinematics (displacement, velocity, and acceleration) during complex movement tasks; and (3) spinal proprioception. The assessment of higher order kinematics during complex movement tasks is the most highly researched and the most successful in describing differences between the populations. The use of simple end range of motion appears questionable, while assessing spinal proprioception is the least researched, yet shows potential in highlighting differences between low back sufferers and asymptomatics. CONCLUSION: Current kinematic biomechanical assessment techniques are capable of identifying functional differences between low back pain populations and controls. The use and validity of the majority of these techniques as outcome measures are currently unknown, yet may be valuable in generating functional diagnoses, evaluating the mechanisms of current therapies, and prescribing specific rehabilitation programs.

Biomechanical Phenomena↗

Psychometric update of the Functional Interference Estimate: a brief measure of pain functional interference.

The Functional Interference Estimate (FIE) is a brief, 5-item self-report measure that assesses the degree to which pain interferes with daily functioning. While the FIE has demonstrated reliability and validity with a small normative sample, not much is known about its reliability and validity with a broad sample of individuals with pain. The current study presents FIE score means, variability estimates, reliability and validity data based on a large sample (n = 1,337) of primary care patients who report problematic pain. The FIE has excellent internal consistency and appears to have strong convergent validity with other well-established measures of function (e.g., SF-36 and Dartmouth COOP Charts). Because of its brevity and flexibility, the FIE may be a useful self-report measure of pain functional interference in clinical research on pain.

Activities of Daily Living↗

Functional multi-layer perceptron: a non-linear tool for functional data analysis.

In this paper, we study a natural extension of multi-layer perceptrons (MLP) to functional inputs. We show that fundamental results for classical MLP can be extended to functional MLP. We obtain universal approximation results that show the expressive power of functional MLP is comparable to that of numerical MLP. We obtain consistency results, which imply that the estimation of optimal parameters for functional MLP is statistically well defined. We finally show on simulated and real world data that the proposed model performs in a very satisfactory way.

Algorithms↗

A functional neuroimaging study of motivation and executive function.

Executive functions, such as working memory, must intersect with functions that determine value for the organism. Functional imaging work in humans and single-unit recordings in non-human primates provide evidence that PFC might integrate motivational context with working memory. With functional magnetic resonance imaging (fMRI), we addressed the question of motivation and working memory, using a trial-related design in an object-working memory task. The design permitted the analysis of BOLD signal at separate stages, corresponding to encoding, maintenance, and retrieval. Subjects were motivated by a financial incentive during the task, such that they could gain a high or a low reward. The two different levels of reward also entailed greater or lesser risk of losing money for incorrect responses. In the high, relative to the low, reward condition, subjects shifted response bias, and showed a trend to greater sensitivity. We found main effects in fMRI BOLD signal for reward, which overlapped with BOLD effects for maintenance of information, in the right superior frontal sulcus and bilateral intraparietal sulcus. We also found an interaction between reward and retrieval from working memory in the right dorsolateral prefrontal cortex. Main effects of load and reward occurred in adjacent regions of the ventrolateral PFC during retrieval. The data demonstrate that when subjects perform a simple working memory task, financial incentives motivate performance and interact with some of the same neural networks that process various stages of working memory. Areas of overlap and interaction may integrate information about value, or they may represent a general effect of motivation increasing neural effort.

Adult↗

Functional subdivisions within anterior cingulate cortex and their relationship to autonomic nervous system function.

The anterior cingulate cortex (ACC) has diverse functions and several functional subdivisions. This study implemented a counting Stroop task that presented incongruent (INC) and congruent (CON) stimuli at two speeds to probe dorsal (dACC) and ventral (vACC) using functional magnetic resonance imaging (fMRI). Eighteen healthy subjects completed the task twice: once outside the scanner while heart rate variability (HRV) was recorded and once during fMRI. In both sessions, subjects completed two runs. Stimuli were presented every 2.0 s in one run and every 1.5 s in the other. fMRI data analysis revealed two important findings. First, by computing differential activation between INC and CON stimuli, a cluster of activation related to response inhibition was observed in the left dACC. Additionally, by calculating the interaction of speed with stimulus congruency, a cluster of activation was observed in the left vACC. This activation correlated significantly with high-frequency HRV (P < 0.02 for CON and P < 0.003 for INC) and represents the parasympathetic modulatory role of the vACC. This study supports the notion of functional subdivisions within the ACC and links the processes of cognitive interference and parasympathetic modulation with activation in specific subregions of the ACC, a structure that is critical for the interface between cognition and emotion.

Adult↗

Estimation of the cortical functional connectivity with the multimodal integration of high-resolution EEG and fMRI data by directed transfer function.

Nowadays, several types of brain imaging device are available to provide images of the functional activity of the cerebral cortex based on hemodynamic, metabolic, or electromagnetic measurements. However, static images of brain regions activated during particular tasks do not convey the information of how these regions communicate with each other. In this study, advanced methods for the estimation of cortical connectivity from combined high-resolution electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data are presented. These methods include a subject's multicompartment head model (scalp, skull, dura mater, cortex) constructed from individual magnetic resonance images, multidipole source model, and regularized linear inverse source estimates of cortical current density. Determination of the priors in the resolution of the linear inverse problem was performed with the use of information from the hemodynamic responses of the cortical areas as revealed by block-designed (strength of activated voxels) fMRI. We estimate functional cortical connectivity by computing the directed transfer function (DTF) on the estimated cortical current density waveforms in regions of interest (ROIs) on the modeled cortical mantle. The proposed method was able to unveil the direction of the information flow between the cortical regions of interest, as it is directional in nature. Furthermore, this method allows to detect changes in the time course of information flow between cortical regions in different frequency bands. The reliability of these techniques was further demonstrated by elaboration of high-resolution EEG and fMRI signals collected during visually triggered finger movements in four healthy subjects. Connectivity patterns estimated for this task reveal an involvement of right parietal and bilateral premotor and prefrontal cortical areas. This cortical region involvement resembles that revealed in previous studies where visually triggered finger movements were analyzed with the use of separate EEG or fMRI measurements.

Adult↗

The psychological, neurochemical and functional neuroanatomical mediators of the effects of positive and negative mood on executive functions.

In this review we evaluate the cognitive and neural effects of positive and negative mood on executive function. Mild manipulations of negative mood appear to have little effect on cognitive control processes, whereas positive mood impairs aspects of updating, planning and switching. These cognitive effects may be linked to neurochemistry: with positive mood effects mediated by dopamine while negative mood effects may be mediated by serotonin levels. Current evidence on the effects of mood on regional brain activity during executive functions, indicates that the prefrontal cortex is a recurrent site of integration between mood and cognition. We conclude that there is a disparity between the importance of this topic and awareness of how mood affects, executive functions in the brain. Most behavioural and neuroimaging studies of executive function in normal samples do not explore the potential role of variations in mood, yet the evidence we outline indicates that even mild fluctuations in mood can have a significant influence on neural activation and cognition.

Affect↗

Prefrontal cognitive functions in stabilized first-episode patients with schizophrenia spectrum disorders: a dissociation between dorsolateral and orbitofrontal functioning.

Specific prefrontal cognitive impairments have been reported in first-episode and chronic schizophrenia. We sought to investigate potential impairments in specific prefrontal cortical cognitive functions among stabilized patients with a first-episode of schizophrenia. A sample of 80 individuals with a first-episode of schizophrenia spectrum disorders and 22 healthy volunteers underwent a neurocognitive battery assessing orbitofrontal (OFC) [The Iowa Gambling Task (GT)], and dorsolateral prefrontal (DLPFC) functions (WAIS III Backward digits, verbal fluency test (FAS), and Trail Making Test). Cognitive data were obtained following stabilization of acute psychotic symptoms. Clinical symptoms after six weeks of treatment were assessed by using the SAPS and SANS scales. While there were no significant group differences in overall scores and in the profile of progress of performance along periods on the GT, patient group showed a significant impairment when performing DLPFC tasks. Only FAS score was correlated to the severity of negative symptomatology. The OFC functions are unimpaired at the early phases of psychosis and in contrast there is a significant deficit in DLPFC functions in first-episode of schizophrenia.

Adult↗

Pretransplant calcium levels have no predictive value for delayed graft function, long-term graft function, cardiovascular events, or graft and patient survival in renal transplantation.

BACKGROUND: Disorders of calcium homeostasis are one of the most common problems in patients with end-stage renal disease (ESRD). Elevated calcium levels increase the incidence of cardiovascular mortality in ESRD patients, and appear to be a risk factor for the occurrence of delayed graft function (DGF) after kidney transplantation. Therefore, we investigated the impact of pretransplant serum calcium levels on outcomes after kidney transplantation: DGF, acute rejection, graft function, and survival, as well as the incidence of cardiovascular events. METHODS: We studied 285 patients (96.9% of all transplanted patients) who underwent their first transplantation between 1995 and 2004. Demographic data were extracted from hospital records or were documented during follow-up; serum samples were collected at the time of transplantation. RESULTS: In our cohort the incidence of DGF was 16.5% and 35.4% of acute rejection episodes (ARE). However, pretransplant calcium levels were not related to DGF or ARE in our patient cohort. Furthermore, there was no correlation between pretransplant serum calcium level with the incidence of cardiovascular events or mortality, as well as graft function or survival. CONCLUSION: In our study population pretransplant calcium levels showed no effect on DGF, ARE rate, the occurrence of cardiovascular events or death, renal graft function, or survival. Therefore, pretransplant calcium level is not a helpful marker for risk stratification at the time of transplantation.

Biomarkers↗

Restoration of endocrine function and fertility with a tubo-ovarian autotransplant as the anatomical-functional unit in rabbits using a vascular microsurgical technique.

Infertility has been considered a global public health problem in many countries worldwide. Our objective was to restore endocrine function and fertility in tubal-oophorectomized rabbits using an orthotopic tubal-ovarian vascularized autotransplant model as the anatomical-functional unit while employing a microvascular surgical technique. Twenty New Zealand white (NZW) sexually mature female rabbits and four male NZW rabbits of proven fertility were divided into two study groups. In group I (n = 10), a left salpingo-oophorectomy was performed. Group II (n = 10) was subjected to a bilateral salpingo-oophorectomy, plus a right orthotopic tubal-ovarian autotransplant. Our testing variables were vascular and tubal-anastomoses permeability, estradiol (E2) and progesterone (P4) serum levels, pregnancy, number of offspring, histopathological study of the uteri, fallopian tubes, and ovaries. One hundred percent immediate permeability of the tubal anastomoses was achieved, while late permeability was found to be 64%. Immediate permeability of vascular anastomoses was 90%, and late permeability was recorded at 80%. E2 serum levels in both groups at different times showed no statistically significant differences. In the case of P4, a small difference was found during pregnancy, especially greater in the control group (P < .05). In the autotransplanted group, four rabbits became pregnant (44%). Endocrine function and fertility were restored in the rabbits with the tubal-ovarian transplant as the anatomical-functional unit. The use of isotransplants and allotransplants should be considered a therapeutic alternative in the infertile woman with irreparable bilateral tubal damage, ovarian dysgenesis, surgical absence of ovaries and fallopian tubes, or when the conventional IVF/TE in these cases has been unsuccessful.

Anastomosis, Surgical↗