Atypical Dynamic Functional Network Connectivity State Engagement during Social-Emotional Processing in Schizophrenia and Autism.

Autism spectrum disorder (ASD) and schizophrenia (SZ) are separate clinical entities but share deficits in social-emotional processing and static neural functional connectivity patterns. We compared patients' dynamic functional network connectivity (dFNC) state engagement with typically developed (TD) individuals during social-emotional processing after initially characterizing such dynamics in TD. Young adults diagnosed with ASD (n = 42), SZ (n = 41), or TD (n = 55) completed three functional MRI runs, viewing social-emotional videos with happy, sad, or neutral content. We examined dFNC of 53 spatially independent networks extracted using independent component analysis and applied k-means clustering to windowed dFNC matrices, identifying four unique whole-brain dFNC states. TD showed differential engagement (fractional time, mean dwell time) in three states as a function of emotion. During Happy videos, patients spent less time than TD in a happy-associated state and instead spent more time in the most weakly connected state. During Sad videos, only ASD spent more time than TD in a sad-associated state. Additionally, only ASD showed a significant relationship between dFNC measures and alexithymia and social-emotional recognition task scores, potentially indicating different neural processing of emotions in ASD and SZ. Our results highlight the importance of examining temporal whole-brain reconfiguration of FNC, indicating engagement in unique emotion-specific dFNC states.

Default mode network modulation by mentalizing in young adults with autism spectrum disorder or schizophrenia.

Schizophrenia and autism spectrum disorder (ASD) are nosologically distinct neurodevelopmental disorders with similar deficits in social cognition, including the ability to form mental representations of others (i.e., mentalizing). However, the extent of patient deficit overlap in underlying neural mechanisms is unclear. Our goal was to examine deficits in mentalizing task-related (MTR) activity modulation in schizophrenia and ASD and the relationship of such deficits with social functioning and psychotic symptoms in patients. Adults, ages 18-34, diagnosed with either ASD or schizophrenia, and typically developed controls (n = 30/group), performed an interactive functional MRI Domino task. Using independent component analysis, we analyzed game intervals known to stimulate mentalizing in the default mode network (DMN), i.e., medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), precuneus, and temporoparietal junction (TPJ), for group differences in MTR activity and associations between MTR activity and social and psychosis measures. Compared to controls, both schizophrenia and ASD groups showed MTR activity deficits in PCC and TPJ. In TPJ and MPFC, MTR activity modulation was associated with social communication impairments only in ASD. In precuneus, MTR activity was associated with increased self-reported fantasizing only in schizophrenia. In schizophrenia, we found no indication of over-mentalizing activity or an association between MTR activity and psychotic symptoms. Results suggest shared neural deficits between ASD and schizophrenia in mentalizing-associated DMN regions; however, neural organization might correspond to different dimensional social deficits. Our results therefore indicate the importance of examining both categorical-clinical diagnosis and social functioning dimensional constructs when examining neural deficits in schizophrenia and ASD.

Determining the light scattering and absorption parameters from forward-directed flux measurements in cardiac tissue.

We describe a method to accurately measure the light scattering model parameters from forward-directed flux (FDF) measurements carried out with a fiber-optic probe (optrode). Improved determination of light scattering parameters will, in turn, permit better modeling and interpretation of optical mapping in the heart using voltage-sensitive dyes. Using our optrode-based system, we carried out high spatial resolution measurements of FDF in intact and homogenized cardiac tissue, as well as in intralipid-based tissue phantoms. The samples were illuminated with a broad collimated beam at 660 and 532 nm. Measurements were performed with a plunge fiber-optic probe (NA=0.22) at a spatial resolution of up to 10 µm. In the vicinity of the illuminated surface, the FDF consistently manifested a fast decaying exponent with a space constant comparable with the decay rate of ballistic photons. Using a Monte Carlo model, we obtained a simple empirical formula linking the rate of the fast exponent to the scattering coefficient, the anisotropy parameter g, and the numerical aperture of the probe. The estimates of scattering coefficient based on this formula were validated in tissue phantoms. Potential applications of optical fiber-based FDF measurements for the evaluation of optical parameters in turbid media are discussed.

Adolescent maturation of the relationship between cortical gyrification and cognitive ability.

There are changes to the degree of cortical folding from gestation through adolescence into young adulthood. Recent evidence suggests that degree of cortical folding is linked to individual differences in general cognitive ability in healthy adults. However, it is not yet known whether age-related cortical folding changes are related to maturation of specific cognitive abilities in adolescence. To address this, we examined the relationship between frontoparietal cortical folding as measured by a Freesurfer-derived local gyrification index (lGI) and performance on subtests from the Wechsler Abbreviated Scale of Intelligence and scores from Conner's Continuous Performance Test-II in 241 healthy adolescents (ages 12-25 years). We hypothesized that age-related lGI changes in the frontoparietal cortex would contribute to cognitive development. A secondary goal was to explore if any gyrification-cognition relationships were either test-specific or sex-specific. Consistent with previous studies, our results showed a reduction of frontoparietal local gyrification with age. Also, as predicted, all cognitive test scores (i.e., Vocabulary, Matrix Reasoning, the CPT-II Commission, Omission, Variabiltiy, d') showed age × cognitive ability interaction effects in frontoparietal and temporoparietal brain regions. Mediation analyses confirmed a causal role of age-related cortical folding changes only for CPT-II Commission errors. Taken together, the results support the functional significance of cortical folding, as well as provide the first evidence that cortical folding maturational changes play a role in cognitive development.

Repetitive transcranial magnetic stimulation for generalised anxiety disorder: a pilot randomised, double-blind, sham-controlled trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) holds promise for treating generalised anxiety disorder (GAD) but has only been studied in uncontrolled research. AIMS: This is the first randomised controlled trial (clinicaltrials.gov: NCT01659736) to investigate the efficacy and neural correlates of rTMS in GAD. METHOD: Twenty 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). RESULTS: Response 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. CONCLUSIONS: Findings provide preliminary evidence that rTMS may improve GAD symptoms in association with modifying neural activity in the stimulation site.

Specific default mode subnetworks support mentalizing as revealed through opposing network recruitment by social and semantic FMRI tasks.

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.

Relationships between reward sensitivity, risk-taking and family history of alcoholism during an interactive competitive fMRI task.

BACKGROUND: Individuals with a positive family history for alcoholism (FHP) have shown differences from family-history-negative (FHN) individuals in the neural correlates of reward processing. FHP, compared to FHN individuals, demonstrate relatively diminished ventral striatal activation during anticipation of monetary rewards, and the degree of ventral striatal activation shows an inverse correlation with specific impulsivity measures in alcohol-dependent individuals. Rewards in socially interactive contexts relate importantly to addictive propensities, yet have not been examined with respect to how their neural underpinnings relate to impulsivity-related measures. Here we describe impulsivity measures in FHN and FHP individuals as they relate to a socially interactive functional magnetic resonance imaging (fMRI) task. METHODS: Forty FHP and 29 FHN subjects without histories of Axis-I disorders completed a socially interactive Domino task during functional magnetic resonance imaging and completed self-report and behavioral impulsivity-related assessments. RESULTS: FHP compared to FHN individuals showed higher scores (p = .004) on one impulsivity-related factor relating to both compulsivity (Padua Inventory) and reward/punishment sensitivity (Sensitivity to Punishment/Sensitivity to Reward Questionnaire). Multiple regression analysis within a reward-related network revealed a correlation between risk-taking (involving another impulsivity-related factor, the Balloon Analog Risk Task (BART)) and right ventral striatum activation under reward >punishment contrast (p<0.05 FWE corrected) in the social task. CONCLUSIONS: Behavioral risk-taking scores may be more closely associated with neural correlates of reward responsiveness in socially interactive contexts than are FH status or impulsivity-related self-report measures. These findings suggest that risk-taking assessments be examined further in socially interactive settings relevant to addictive behaviors.

Mentalizing and motivation neural function during social interactions in autism spectrum disorders.

Autism Spectrum Disorders (ASDs) are characterized by core deficits in social functions. Two theories have been suggested to explain these deficits: mind-blindness theory posits impaired mentalizing processes (i.e. decreased ability for establishing a representation of others' state of mind), while social motivation theory proposes that diminished reward value for social information leads to reduced social attention, social interactions, and social learning. Mentalizing and motivation are integral to typical social interactions, and neuroimaging evidence points to independent brain networks that support these processes in healthy individuals. However, the simultaneous function of these networks has not been explored in individuals with ASDs. We used a social, interactive fMRI task, the Domino game, to explore mentalizing- and motivation-related brain activation during a well-defined interval where participants respond to rewards or punishments (i.e. motivation) and concurrently process information about their opponent's potential next actions (i.e. mentalizing). Thirteen individuals with high-functioning ASDs, ages 12-24, and 14 healthy controls played fMRI Domino games against a computer-opponent and separately, what they were led to believe was a human-opponent. Results showed that while individuals with ASDs understood the game rules and played similarly to controls, they showed diminished neural activity during the human-opponent runs only (i.e. in a social context) in bilateral middle temporal gyrus (MTG) during mentalizing and right Nucleus Accumbens (NAcc) during reward-related motivation (Pcluster < 0.05 FWE). Importantly, deficits were not observed in these areas when playing against a computer-opponent or in areas related to motor and visual processes. These results demonstrate that while MTG and NAcc, which are critical structures in the mentalizing and motivation networks, respectively, activate normally in a non-social context, they fail to respond in an otherwise identical social context in ASD compared to controls. We discuss implications to both the mind-blindness and social motivation theories of ASD and the importance of social context in research and treatment protocols.

Reward-related dorsal striatal activity differences between former and current cocaine dependent individuals during an interactive competitive game.

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).

Cortical thickness and folding deficits in conduct-disordered adolescents.

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. On the basis of current frontotemporal 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 24 control and 19 CD participants aged 12 to 18 years, matched by 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: The CD participants, compared with control subjects, 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.

Dual excitation wavelength epifluorescence imaging of transmural electrophysiological properties in intact hearts.

BACKGROUND: Epifluorescence imaging using voltage-sensitive dyes has provided unique insights into cardiac electrical activity and arrhythmias. However, conventional dyes use blue-green excitation light, which has limited depth penetration. OBJECTIVE: The aim of this study was to demonstrate that combining a short and a long excitation wavelength using near-infrared (NIR) dyes allows for epifluorescence imaging of transmural electrophysiological properties in intact hearts. METHODS: Epifluorescence imaging was performed in rat hearts (N = 11) using DI-4-ANEPPS and the NIR dye DI-4-ANBDQBS. Activation and action potential duration (APD) patterns were investigated at 2 excitation wavelengths (530 and 660 nm) after epicardial stimulation at various cycle lengths (160 to 70 ms). RESULTS: Optical action potential upstrokes acquired with 660-nm excitation of DI-4-ANBDQBS were significantly longer than upstrokes obtained with 530-nm excitation of DI-4-ANEPPS (P < .001). Comparison of activation maps showed counterclockwise rotation of isochrones consistent with a transmural rotation of myofibers. Pronounced APD modulation by the activation sequence was observed at both excitation wavelengths. Significantly prolonged APDs (P = .016) and steeper APD restitution curves were found with DI-4-ANBDQBS (660-nm excitation) when compared with DI-4-ANEPPS (530-nm excitation). Dual excitation wavelength experiments using solely DI-4-ANBDQBS yielded similar results. Monophasic action potential recordings showed prolonged APD and steeper APD restitution curves in the endocardium, indicating that 660-nm excitation provides a significant endocardial contribution to the signal. Three-dimensional computer simulations confirmed our findings. CONCLUSION: Dual excitation wavelength epifluorescence allows detecting transmural heterogeneity in intact hearts. It therefore has the potential to become an important tool in experimental cardiac electrophysiology.

Reconstructing subsurface electrical wave orientation from cardiac epi-fluorescence recordings: Monte Carlo versus diffusion approximation.

The development of voltage-sensitive dyes has revolutionized cardiac electrophysiology and made optical imaging of cardiac electrical activity possible. Photon diffusion models coupled to electrical excitation models have been successful in qualitatively predicting the shape of the optical action potential and its dependence on subsurface electrical wave orientation. However, the accuracy of the diffusion equation in the visible range, especially for thin tissue preparations, remains unclear. Here, we compare diffusion and Monte Carlo (MC) based models and we investigate the role of tissue thickness. All computational results are compared to experimental data obtained from intact guinea pig hearts. We show that the subsurface volume contributing to the epi-fluorescence signal extends deeper in the tissue when using MC models, resulting in longer optical upstroke durations which are in better agreement with experiments. The optical upstroke morphology, however, strongly correlates to the subsurface propagation direction independent of the model and is consistent with our experimental observations.

Extracting intramural wavefront orientation from optical upstroke shapes in whole hearts.

Information about intramural propagation of electrical excitation is crucial to understanding arrhythmia mechanisms in thick ventricular muscle. There is currently a controversy over whether it is possible to extract such information from the shape of the upstroke in optical mapping recordings. We show that even in the complex geometry of a whole guinea pig heart, optical upstroke morphology reveals the 3D wavefront orientation near the surface. To characterize the upstroke morphology, we use V(F)(*), the fractional level at which voltage-sensitive fluorescence, V(F), has maximal time derivative. Low values of V(F)(*)( approximately 0.2) indicate a wavefront moving away from the surface, high values of V(F)(*) ( approximately 0.6) a wavefront moving toward the surface, and intermediate values of V(F)(*) ( approximately 0.4) a wavefront moving parallel to the surface. We further performed computer simulations using Luo-Rudy II electrophysiology and a simplified 3D geometry. The simulated V(F)(*) maps for free wall and apical stimulations as well as for sinus rhythm are in good quantitative agreement with the averaged experimental results. Furthermore, computer simulations show that the effect of the curvature of the heart on wave propagation is negligible.

What can we learn from the optically recorded epicardial action potential?

Optical mapping using voltage-sensitive fluorescent dyes has become a major tool for studying excitation propagation in the heart. Computational and experimental studies have indicated that the optical upstroke morphology reflects the orientation of the subsurface excitation front. In a recent whole heart computational study performed by Bishop et al. (Bishop, M. J., B. Rodriguez, J. Eason, J. P. Whiteley, N. Trayanova, and D. J. Gavaghan. 2006. Synthesis of voltage-sensitive optical signals: application to panoramic optical mapping. Biophys. J. 90:2938-2945), an example was provided of two different directions of propagation having nevertheless very similar epicardial optical upstrokes. The goal of this comment is to clarify the interpretation of optical upstroke morphologies and reconcile the results obtained by Bishop et al. with previous computational and experimental studies.

Intra-myocardial cusp waves and their manifestation in optical mapping signals.

The rotating fiber orientation within the cardiac wall substantially affects the electrical propagation and can cause intra-myocardial cusp waves. Numerical simulations have shown that the cusps form in layers where propagation is perpendicular to the fiber orientation and lead to complex wave front morphologies. They can travel across layers and break through at the epi- or endocardial surfaces where they cause apparent accelerations of propagation. The validation of these results remains a major experimental challenge. In the present study, we investigate both computationally and experimentally how intramural cusp waves can be detected using optical imaging. Our simulations show that cusps alter the optical upstroke morphology and can be detected well before they reach the surface (up to 1 mm deep). Experiments in Langendorff-perfused guinea pig hearts are consistent with our numerical findings.

Optical action potential upstroke morphology reveals near-surface transmural propagation direction.

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 phi 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 phi. We determined that the level VF* at which the rate of rise of the optical upstroke reaches the maximum linearly depends on phi. 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 VF*<0.5, consistent with theoretical predictions for phi>0. Similarly, we obtained good agreement with theory for plane waves propagating in a direction perpendicular to fibers (VF*>0.5 when phi<0). Finally, during epicardial point stimulation, we discovered characteristic saddle-shaped VF* maps that were in excellent agreement with theoretically predicted changes in phi during wavefront expansion. Our findings should allow for improved interpretation of the results of optical mapping of intact heart preparations.

Epicardial fiber organization in swine right ventricle and its impact on propagation.

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 (n=8) 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 mum 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 microm. At the boundary of this layer, we observed an abrupt change in fiber angle by 64+/-13 degrees followed by a gradual fiber rotation in the underlying layers. In preparations with z(0) <700 microm, 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.

Synthesis of voltage-sensitive fluorescence signals from three-dimensional myocardial activation patterns.

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.