Voltage-sensitive fluorescent dyes are commonly used to measure cardiac electrical activity. Recent studies indicate, however, that optical action potentials (OAPs) recorded from the myocardial surface originate from a widely distributed volume beneath the surface and may contain useful information regarding intramural activation. The first step toward obtaining this information is to predict OAPs from known patterns of three-dimensional (3-D) electrical activity. To achieve this goal, we developed a two-stage model in which the output of a 3-D ionic model of electrical excitation serves as the input to an optical model of light scattering and absorption inside heart tissue. The two-stage model permits unique optical signatures to be obtained for given 3-D patterns of electrical activity for direct comparison with experimental data, thus yielding information about intramural electrical activity. To illustrate applications of the model, we simulated surface fluorescence signals produced by 3-D electrical activity during epicardial and endocardial pacing. We discovered that OAP upstroke morphology was highly sensitive to the transmural component of wave front velocity and could be used to predict wave front orientation with respect to the surface. These findings demonstrate the potential of the model for obtaining useful 3-D information about intramural propagation.

Background Studies of pediatric conduct disorder (CD) have described frontal and temporal lobe structural abnormalities that parallel findings in antisocial adults. The purpose of this study was to examine previously unexplored cortical thickness and folding as markers for brain abnormalities in “pure CD”-diagnosed adolescents. Based on current fronto-temporal theories, we hypothesized that CD youth would have thinner cortex or less cortical folding in temporal and frontal lobes than control subjects. Methods We obtained T1-weighted brain structure images from n=24 control and n=19 CD participants aged 12–18 years, matched by overall gender and age. We measured group differences in cortical thickness and local gyrification index (regional cortical folding measure) using surface-based morphometry with clusterwise correction for multiple comparisons. Results CD participants, when compared with controls, showed both reduced cortical thickness and folding. Thinner cortex was located primarily in posterior brain regions, including left superior temporal and parietal lobes, temporoparietal junction and paracentral lobule, right superior temporal and parietal lobes, temporoparietal junction and precuneus. Folding deficits were located mainly in anterior brain regions and included left insula, ventro- and dorsomedial prefrontal, anterior cingulate and orbitofrontal cortices, temporal lobe, right superior frontal and parietal lobes and paracentral lobule. Conclusions Our findings generally agree with previous CD volumetric studies, but here show the unique contributions of cortical thickness and folding to gray matter reductions in pure CD in different brain regions.

Abstract-The analysis of surface-activation patterns and measurements of conduction velocity in ventricular myocardium is complicated by the fact that the electrical wavefront has a complex 3D shape and can approach the heart surface at various angles. Recent theoretical studies suggest that the optical upstroke is sensitive to the subsurface orientation of the wavefront. Our goal here was to (1) establish the quantitative relationship between optical upstroke morphology and subsurface wavefront orientation using computer modeling and (2) test theoretical predictions experimentally in isolated coronary-perfused swine right ventricular preparations. We show in numerical simulations that by suitable placement of linear epicardial stimulating electrodes, the angle of wavefronts with respect to the heart surface can be controlled. Using this method, we developed theoretical predictions of the optical upstroke shape dependence on . We determined that the level V F * at which the rate of rise of the optical upstroke reaches the maximum linearly depends on . A similar relationship was found in simulations with epicardial point stimulation. The optical mapping data were in good agreement with theory. Plane waves propagating parallel to myocardial fibers produced upstrokes with V F *Ͻ0.5, consistent with theoretical predictions for Ͼ0. Similarly, we obtained good agreement with theory for plane waves propagating in a direction perpendicular to fibers (V F *Ͼ0.5 when Ͻ0). Finally, during epicardial point stimulation, we discovered characteristic saddle-shaped V F * maps that were in excellent agreement with theoretically predicted changes in during wavefront expansion. Our findings should allow for improved interpretation of the results of optical mapping of intact heart preparations. Key Words: optical action potential Ⅲ conduction velocity Ⅲ optical mapping Ⅲ voltage-sensitive dye P atterns of electrical activation within the ventricular wall are determined in large part by the specific 3D organization of myocardial fibers. Histological studies of intact hearts from many species have shown conclusively that myocardial fiber orientation rotates significantly across the heart wall. 1 The total angle of rotation across the myocardial wall can reach 180°. 2 Because of the complex transmural organization of myocardial fibers, an excitation wavefront typically assumes a complex 3D profile that, depending on the mode of stimulation, can approach the myocardial surface at a variety of different angles. [3][4][5][6] For this reason, obtaining accurate quantitative information about the wavefront orientation with respect to the surface is quite important for the interpretation of surface recordings, particularly with regard to measurements of conduction velocity.In a recent modeling study, 7 we discovered that the upstroke morphology of optical action potentials (OAPs) was sensitive to the local subsurface orientation of the excitation wavefront. This suggests that analysis of OAP upstroke morphology may prove useful in determini...

We examine how the structure and function of indirect flight muscle (IFM) and the entire flight system of Drosophila melanogaster are affected by phosphorylation of the myosin regulatory light chain (MLC2). This integrated study uses site-directed mutagenesis to examine the relationship between removal of the myosin light chain kinase (MLCK) phosphorylation site, in vivo function of the flight system (flight tests, wing kinematics, metabolism, power output), isolated IFM fiber mechanics, MLC2 isoform pattern, and sarcomeric ultrastructure. The MLC2 mutants exhibit graded impairment of flight ability that correlates with a reduction in both IFM and flight system power output and a reduction in the constitutive level of MLC2 phosphorylation. The MLC2 mutants have wild-type IFM sarcomere and cross-bridge structures, ruling out obvious changes in the ultrastructure as the cause of the reduced performance. We describe a viscoelastic model of cross-bridge dynamics based on sinusoidal length perturbation analysis (Nyquist plots) of skinned IFM fibers. The sinusoidal analysis suggests the high power output of Drosophila IFM required for flight results from a phosphorylation-dependent recruitment of power-generating cross-bridges rather than a change in kinetics of the power generating step. The reduction in cross-bridge number appears to affect the way mutant flies generate flight forces of sufficient magnitude to keep them airborne. In two MLC2 mutant strains that exhibit a reduced IFM power output, flies appear to compensate by lowering wingbeat frequency and by elevating wingstroke amplitude (and presumably muscle strain). This behavioral alteration is not seen in another mutant strain in which the power output and estimated number of recruited cross-bridges is similar to that of wild type.

BackgroundRepetitive transcranial magnetic stimulation (rTMS) holds promise for treating generalised anxiety disorder (GAD) but has only been studied in uncontrolled research.AimsThis is the first randomised controlled trial (clinicaltrials.gov: NCT01659736) to investigate the efficacy and neural correlates of rTMS in GAD.MethodTwenty five participants (active n = 13; sham, n = 12) enrolled. rTMS was targeted at the right dorsolateral prefrontal cortex (DLPFC, 1 Hz, 90% resting motor threshold).ResultsResponse and remission rates were higher in the active v. sham groups and there were significant group × time interactions for anxiety, worry and depressive symptoms, favouring active v. sham. In addition, right DLPFC activation during a decision-making gambling task increased at post-treatment for active rTMS only, and changes in neuroactivation correlated significantly with changes in worry symptoms.ConclusionsFindings provide preliminary evidence that rTMS may improve GAD symptoms in association with modifying neural activity in the stimulation site.

The ability to attribute mental states to others, or "mentalizing," is posited to involve specific subnetworks within the overall default mode network (DMN), but this question needs clarification. To determine which default mode (DM) subnetworks are engaged by mentalizing processes, we assessed task-related recruitment of DM subnetworks. Spatial independent component analysis (sICA) applied to fMRI data using relatively high-order model (75 components). Healthy participants (n = 53, ages 17-60) performed two fMRI tasks: an interactive game involving mentalizing (Domino), a semantic memory task (SORT), and a resting state fMRI scan. sICA of the two tasks split the DMN into 10 subnetworks located in three core regions: medial prefrontal cortex (mPFC; five subnetworks), posterior cingulate/precuneus (PCC/PrC; three subnetworks), and bilateral temporoparietal junction (TPJ). Mentalizing events increased recruitment in five of 10 DM subnetworks, located in all three core DMN regions. In addition, three of these five DM subnetworks, one dmPFC subnetwork, one PCC/PrC subnetwork, and the right TPJ subnetwork, showed reduced recruitment by semantic memory task events. The opposing modulation by the two tasks suggests that these three DM subnetworks are specifically engaged in mentalizing. Our findings, therefore, suggest the unique involvement of mentalizing processes in only three of 10 DM subnetworks, and support the importance of the dmPFC, PCC/PrC, and right TPJ in mentalizing as described in prior studies.

Abstract-Fiber organization is important for myocardial excitation and contraction. It can be a major factor in arrhythmogenesis and current distribution during defibrillation shocks. In this study, we report the discovery of a previously undetected thin epicardial layer in swine right ventricle (RV) with distinctly different fiber orientation, which significantly affects epicardial propagation. Experiments were conducted in isolated coronary-perfused right ventricular free wall preparations (nϭ8) stained with the voltage-sensitive dye di-4-ANEPPS. Optical signals were recorded from the epicardium with a CCD video camera at 800 fps. Preparations were sectioned parallel to the epicardial surface with a resolution of 50 m or better. To link the histological data with the observed activation patterns, resulting fiber angles were introduced into a 3D computer model to simulate the electrical activation and voltage-dependent optical signals.In all preparations, we detected a thin epicardial layer with almost no depth-dependent fiber rotation. The thickness of this layer (z 0 ) varied from 110 to 930 m. At the boundary of this layer, we observed an abrupt change in fiber angle by 64Ϯ13°followed by a gradual fiber rotation in the underlying layers. In preparations with z 0 Ͻ700 m, optical mapping during epicardial stimulation revealed unusual diamond-and rectangular-shaped activation fronts with two axes of fast conduction. Computer simulations accurately predicted the features of the experimentally recorded activation fronts. The free wall of swine RV has a thin epicardial layer with distinctly different fiber orientation, which can significantly affect propagation and give rise to unusually shaped activation fronts. This is important for understanding electrical propagation in the heart, and further refines the existing knowledge of myocardial fiber architecture. Key Words: myofiber organization Ⅲ optical mapping Ⅲ propagation T he fiber organization of ventricular myocardium is a significant determinant of both its mechanical function and its electrical propagation [1][2][3] Myocardial fiber organization has been implicated in the mechanisms of ventricular arrhythmias as one of the important factors responsible for the stability of 3D reentrant activity. 4 -8 It is also thought to affect current distribution during defibrillation shocks 9,10 and thus affect their odds of failure and success. All this explains the persistent interest in structural aspects of myocardial organization 11,12 and motivates further refining the existing knowledge of myocardial fiber architecture.The characteristic feature of myocardial fiber organization is the gradual counterclockwise rotation of fibers throughout the heart wall 1,13-16 with the total rotation angle from endocardium to epicardium across species ranging from 120°( dog) to 180°(pig). 17,18 Although in general the dependence of fiber rotation on depth is considered well established, information about fiber organization near the epicardial surface remains scarce.There are in...

Cocaine addiction is characterized by impulsivity, impaired social relationships, and abnormal mesocorticolimbic reward processing, but their interrelationships relative to stages of cocaine addiction are unclear. We assessed blood-oxygenation-level dependent (BOLD) signal in ventral and dorsal striatum during functional magnetic resonance imaging (fMRI) in current (CCD; n = 30) and former (FCD; n = 28) cocaine dependent subjects as well as healthy control (HC; n = 31) subjects while playing an interactive competitive Domino game involving risk-taking and reward/punishment processing. Out-of-scanner impulsivity-related measures were also collected. Although both FCD and CCD subjects scored significantly higher on impulsivity-related measures than did HC subjects, only FCD subjects had differences in striatal activation, specifically showing hypoactivation during their response to gains versus losses in right dorsal caudate, a brain region linked to habituation, cocaine craving and addiction maintenance. Right caudate activity in FCD subjects also correlated negatively with impulsivity-related measures of self-reported compulsivity and sensitivity to reward. These findings suggest that remitted cocaine dependence is associated with striatal dysfunction during social reward processing in a manner linked to compulsivity and reward sensitivity measures. Future research should investigate the extent to which such differences might reflect underlying vulnerabilities linked to cocaine-using propensities (e.g., relapses).