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Error monitoring is the metacognitive process by which we are able to detect and signal our errors once a response has been made. Monitoring when the outcome of our actions deviates from the intended goal is crucial for behavior, learning, and the development of higher-order social skills. Here, we explored the neuronal substrates of error monitoring during the integration of facial expression cues using electroencephalography (EEG). Our goal was to investigate the signatures of error monitoring before and after a response execution dependent on the integration of facial cues. We followed the hypothesis of midfrontal theta as a robust neuronal marker of error monitoring since it has been consistently described as a mechanism to signal the need for cognitive control. Also, we hypothesized that EEG frequency-domain components might bring advantage to study error monitoring in complex scenarios as it carries information from locked and non-phase-locked signals. A challenging go/no-go saccadic paradigm was applied to elicit errors: integration of facial emotional signals and gaze direction was required to solve it. EEG data were acquired from twenty healthy participants and analyzed at the level of theta band activity during response preparation and execution. Although theta modulation has been consistently demonstrated during error monitoring, it is still unclear how early it starts to occur. We found theta power differences at midfrontal channels between correct and error trials. Theta was higher immediately after erroneous responses. Moreover, before response initiation we observed the opposite: lower theta preceding errors. These results suggest theta band activity not only as an index of error monitoring, which is needed to enhance cognitive control, but also as a requisite for success. This study adds to previous evidence for the role of theta band in error monitoring processes by revealing error-related patterns even before response execution in complex tasks, and using a paradigm requiring the integration of facial expression cues.

BackgroundIt has been claimed that the retina can be used as a window to study brain disorders. However, concerning Alzheimer’s disease (AD), it still remains controversial whether changes occurring in the brain and retina are associated. We aim to understand when changes start appearing in the retina and brain, how changes progress, and if they are correlated.MethodsWe carried out a unique longitudinal study, at 4, 8, 12, and 16 months of age, in a triple transgenic mouse model of AD (3×Tg-AD), which mimics pathological and neurobehavioral features of AD, as we have already shown. Retinal structure and physiology were evaluated in vivo using optical coherence tomography and electroretinography. Brain visual cortex structure was evaluated in vivo using magnetic resonance imaging.ResultsThe retinal thickness of 3×Tg-AD decreased, at all time points, except for the outer nuclear layer, where the opposite alteration was observed. Amplitudes in scotopic and photopic responses were increased throughout the study. Similarly, higher amplitude and lower phase values were observed in the photopic flicker response. No differences were found in the activity of retinal ganglion cells. Visual cortex gray matter volume was significantly reduced.ConclusionsOur results show that this animal model shows similar neural changes in the retina and brain visual cortex, i.e., retinal and brain thinning. Moreover, since similar changes occur in the retina and brain visual cortex, these observations support the possibility of using the eye as an additional tool (noninvasive) for early AD diagnosis and therapeutic monitoring.

Nonalcoholic fatty liver disease (NAFLD) is caused by excessive liver lipid accumulation, but insulin resistance is specifically associated with impaired lipid saturation, oxidation, and storage (esterification), besides increased de novo lipogenesis. We hypothesized that dietary glycotoxins could impair hepatic lipid metabolism in obesity contributing to lipotoxicity-driven insulin resistance and thus to the onset of nonalcoholic steatohepatitis (NASH). In diet-induced obese rats with methylglyoxal-induced glycation, magnetic resonance spectroscopy, mass spectrometry, and gas chromatography were used to assess liver composition in fatty acyl chains and phospholipids. High-fat diet-induced obesity increased liver lipid fraction and suppressed de novo lipogenesis but did not change fatty acid esterification and saturation or insulin sensitivity. Despite a similar increase in total lipid fraction when supplementing the high-fat diet with dietary glycotoxins, impairment in the suppression of de novo lipogenesis and decreased fatty acid unsaturation and esterification were observed. Moreover, glycotoxins also decreased polyunsaturated cardiolipins and caused oxidative stress, portal inflammation, and insulin resistance in high-fat diet-induced obese rats. Dietary glycated products do not change total lipid levels in the liver of obese rats but dramatically modify the lipidemic profile, leading to oxidative stress, hepatic lipotoxicity, and insulin resistance in obesity and thus contribute to the onset of NASH.

Face perception plays an important role in our daily social interactions, as it is essential to recognize emotions. The N170 Event Related Potential (ERP) component has been widely identified as a major face-sensitive neuronal marker. However, despite extensive investigations conducted to examine this electroencephalographic pattern, there is yet no agreement regarding its sensitivity to the content of facial expressions.Here, we aim to clarify the EEG signatures of the recognition of facial expressions by investigating ERP components that we hypothesize to be associated with this cognitive process. We asked the question whether the recognition of facial expressions is encoded by the N170 as weel as at the level of P100 and P250. In order to test this hypothesis, we analysed differences in amplitudes and latencies for the three ERPs, in a sample of 20 participants. A visual paradigm requiring explicit recognition of happy, sad and neutral faces was used. The facial cues were explicitly controlled to vary only regarding mouth and eye components. We found that non neutral emotion expressions elicit a response difference in the amplitude of N170 and P250. In contrast with the P100, there by excluding a role for low level factors.Our study brings new light to the controversy whether emotional face expressions modulate early visual response components, which have been often analysed apart. The results support the tenet that neutral and emotional faces evoke distinct N170 patterns, but go further by revealing that this is also true for P250, unlike the P100.

An emergent research area in software engineering and software reliability is the use of wearable biosensors to monitor the cognitive state of software developers during software development tasks. The goal is to gather physiologic manifestations that can be linked to error-prone scenarios related to programmers’ cognitive states. In this paper we investigate whether electroencephalography (EEG) can be applied to accurately identify programmers’ cognitive load associated with the comprehension of code with different complexity levels. Therefore, a controlled experiment involving 26 programmers was carried. We found that features related to Theta, Alpha, and Beta brain waves have the highest discriminative power, allowing the identification of code lines and demanding higher mental effort. The EEG results reveal evidence of mental effort saturation as code complexity increases. Conversely, the classic software complexity metrics do not accurately represent the mental effort involved in code comprehension. Finally, EEG is proposed as a reference, in particular, the combination of EEG with eye tracking information allows for an accurate identification of code lines that correspond to peaks of cognitive load, providing a reference to help in the future evaluation of the space and time accuracy of programmers’ cognitive state monitored using wearable devices compatible with software development activities.

While dynamic ocular motor abnormalities (e.g., gaze-evoked nystagmus (GEN), low optokinetic nystagmus (OKN), pursuit and vestibulo-ocular reflex (VOR) gains, and dysmetric saccades) have been shown to be potential biomarkers in spinocerebellar ataxia type 3 (SCA3), the value of static abnormalities (e.g., convergent [esodeviation] and divergent strabismus [exodeviation]) is unknown. Moreover, studies on dynamic abnormalities in SCA3 usually do not take into account the existence of potential abduction-adduction asymmetries in patients with degenerative ataxia. Thirty-eight patients with genetically confirmed SCA3 (24 females; mean age ± SD, 49.8± 12.2 years) and 22 healthy controls (12 females, p = 0.589; mean age ± SD, 50.7± 12.5 years, p = 0.651) underwent clinical and video-oculographic assessment. A p value 0.002 (between- and within-group analyses) and 0.001 (correlation analysis) was considered significant. Patients showed larger esodeviation at distance (p 0.001), became more esodeviated in lateral gaze (p 0.001), and their near exodeviation correlated with scale for the assessment and rating of ataxia (SARA) score (p = 0.004). Pursuit, OKN, and VOR gains were lower in patients, both for their adducting and abducting components (p 0.001). Saccades showed higher velocities (p 0.001), abducting saccades showed lower amplitude (p 0.001), and adducting saccades tended to show greater vertical bias (p = 0.018) in patients. Abducting saccades showed relatively lower velocity (p 0.001) and lower amplitude (p = 0.015) than abducting saccades within patients. All dynamic ocular motor abnormalities except saccades correlated with SARA score, CAG repeat number, and/or disease duration (p 0.001). Static and dynamic ocular motor abnormalities are potential biomarkers in SCA3. SCA3 studies using saccades should take into account the existence of potential abduction-adduction asymmetries.

Several studies highlighted the role of insula on several functions and in sexual behavior. This exploratory study examines the relationships among genital responses, brain responses, and eye movements, to disentangle the role played by the anterior and posterior insula during different stages of male sexual response and during visual attention to sexual stimuli. In 19 healthy men, fMRI, eye movement, and penile tumescence data were collected during a visual sexual stimulation task. After a whole-brain analysis comparing neutral and sexual clips and confirming a role for the bilateral insulae, we selected two bilateral seed regions in anterior and posterior insula for functional connectivity analysis. Single-ROI-GLMs were run for the FC target regions. Single-ROI-GLMs were performed based on areas to which participants fixate: "Faces", "Genitals," and "Background" with the contrast "Genitals > Faces". Single-ROI-GLMs with baseline, onset, and sustained PT response for the sexual clips were performed. We found stronger effects for the posterior than the anterior insula. In the target regions of the posterior insula, we found three different pathways: the first involved in visual attention, onset of erection, and sustained erection; the second involved only in the onset of erection, and the third limited to sustained erection. ispartof: SCIENTIFIC REPORTS vol:10 issue:1 ispartof: location:England status: published

The human visual system is constantly processing multiple and often conflicting sensory cues to make perceptual decisions. Given the nonlinear nature of emotion recognition, this often leads to different percepts of the same physical facial expression. Moreover, the state of the emotion recognition system might depend on the trajectory of temporal context, potentially leading to a phenomenon known as perceptual hysteresis. Here, we aimed to explore temporal context-related mechanisms underlying perceptual hysteresis during emotion recognition. We hypothesized that dependence on recent perceptual experience might reveal important clues about the role of short-term memory on the perception of emotional stimuli. Behavioral data were acquired using reality-based, changing emotion expressions morphed from a source to a target emotion with different valences, always passing through a neutral expression. Participants identified the onset and offset of what they perceived as the neutral expression interval. Our results showed that current perception of emotional expression is affected by recent temporal context, thus revealing perceptual hysteresis. We also found a relation between recent perceptual history effects and stimulus emotional Content: The positive valence of the stimulus emotional content appeared to abolish perceptual history effects, whereas negatively loaded stimuli induced clear short-term memory effects and positive hysteresis. Our findings show direct competition between recent perceptual experience and stimulus emotional content during decision making, which affects the formation of current percepts in emotion recognition.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3, the most common dominant spinocerebellar ataxia (SCA) worldwide, is caused by over-repetition of a CAG repeat in the ATXN3/MJD1 gene, which translates into a polyglutamine tract within the ataxin-3 protein. There is no treatment for this fatal disorder. Despite evidence of the safety and efficacy of mesenchymal stromal cells (MSCs) in delaying SCA disease progression in exploratory clinical trials, unanticipated regression of patients to the status prior to treatment makes the investigation of causes and solutions urgent and imperative. In the present study, we compared the efficacy of a single intracranial injection with repeated systemic MSC administration in alleviating the MJD phenotype of two strongly severe genetic rodent models. We found that a single MSC transplantation only produces transient effects, whereas periodic administration promotes sustained motor behavior and neuropathology alleviation, suggesting that MSC therapies should be re-designed to get sustained beneficial results in clinical practice. Furthermore, MSC promoted neuroprotection, increased the levels of GABA and glutamate, and decreased the levels of Myo-inositol, which correlated with motor improvements, indicating that these metabolites may serve as valid neurospectroscopic biomarkers of disease and treatment. This study makes important contributions to the design of new clinical approaches for MJD and other SCAs/polyglutamine disorders.

Software programming is a complex and relatively recent human activity, involving the integration of mathematical, recursive thinking and language processing. The neural correlates of this recent human activity are still poorly understood. Error monitoring during this type of task, requiring the integration of language, logical symbol manipulation and other mathematical skills, is particularly challenging. We therefore aimed to investigate the neural correlates of decision-making during source code understanding and mental manipulation in professional participants with high expertise. The present fMRI study directly addressed error monitoring during source code comprehension, expert bug detection and decision-making. We used C code, which triggers the same sort of processing irrespective of the native language of the programmer. We discovered a distinct role for the insula in bug monitoring and detection and a novel connectivity pattern that goes beyond the expected activation pattern evoked by source code understanding in semantic language and mathematical processing regions. Importantly, insula activity levels were critically related to the quality of error detection, involving intuition, as signalled by reported initial bug suspicion, prior to final decision and bug detection. Activity in this salience network (SN) region evoked by bug suspicion was predictive of bug detection precision, suggesting that it encodes the quality of the behavioral evidence. Connectivity analysis provided evidence for top-down circuit “reutilization” stemming from anterior cingulate cortex (BA32), a core region in the SN that evolved for complex error monitoring such as required for this type of recent human activity. Cingulate (BA32) and anterolateral (BA10) frontal regions causally modulated decision processes in the insula, which in turn was related to activity of math processing regions in early parietal cortex. In other words, earlier brain regions used during evolution for other functions seem to be reutilized in a top-down manner for a new complex function, in an analogous manner as described for other cultural creations such as reading and literacy. Electronic supplementary material The online version of this article (10.1007/s11682-018-9885-1) contains supplementary material, which is available to authorized users.

This study aimed to explore the differential role of the frontoparietal network in processing different visual object categories, matched for difficulty level, during a 1-back paradigm. To achieve this goal, we first mapped the effort-related frontoparietal saliency network, by contrasting activation elicited by face, object, place, body and verbal stimulus categories, which were matched for performance level, and speed of processing, with difficult scrambled stimuli. We then computed the weight of object predictors on that specific network, using an independent orthogonal analysis. Overall, our results demonstrated that face (and to some extent also places) stimuli were associated with lower processing load in regions of the frontoparietal network comparing to other visual categories, suggesting that face/place processing does require to a much smaller extent the recruitment of the frontoparietal control network than any other object categories. Thus, face detection and place detection seem to be routed in specific neuronal systems that readily encode the holistic nature of this type of objects. We conclude that the more limited recruitment of frontoparietal networks reflects the automaticity of face and place processing and their smaller dependence on general capacity limits.

BACKGROUND Type-2 diabetes mellitus (T2DM) is a metabolic disorder with a broad range of complications in the brain that depend on the conditions that precede its onset, such as obesity and metabolic syndromes. It has been suggested that neurotransmitter and metabolic perturbations may emerge even before the early stages of T2DM and that high-caloric intake could adversely influence the brain in such states. Notwithstanding, evidence for neurochemical and structural alterations in these conditions are still sparse and controversial. PURPOSE To evaluate the influence of high-fat diet in the neurochemical profile and structural integrity of the rodent brain. STUDY TYPE Prospective. SUBJECTS Wistar rats (n = 12/group). FIELD STRENGTH/SEQUENCE A PRESS, ISIS, RARE, and EPI sequences were performed at 9.4T. ASSESSMENT Neurochemical and structural parameters were assessed by magnetic resonance spectroscopy, voxel-based morphometry, volumetry, and diffusion tensor imaging. STATISTICAL TESTS Measurements were compared through Student and Mann-Whitney tests. Pearson correlation was used to assess relationships between parameters. RESULTS Animals submitted to high-caloric intake gained weight (P = 0.003) and developed glucose intolerance (P

Methamphetamine (METH) abuse/misuse is a worldwide problem, and despite extensive characterization of its neurotoxicity over the last years, many questions remain unanswered. Recently, it was shown that METH compromises the blood-brain barrier (BBB) and causes a disturbance in the water homeostasis leading to brain edema. Importantly, water transport at BBB is regulated by water channels, aquaporins (AQPs), with AQP4 being expressed in astrocytic end-feet surrounding brain endothelium. Thus, the main goal of this work was to unravel the role of AQP4 under conditions of METH consumption. Our results show that METH (4× 10 mg/kg, 2 h apart, i.p.) interferes with AQP4 protein levels causing brain edema and BBB breakdown in both mice striatum and hippocampus, which culminated in locomotor and motivational impairment. Furthermore, these effects were prevented by pharmacological blockade of AQP4 with a specific inhibitor (TGN-020). Moreover, siRNA knockdown of this water channel protected astrocytes from METH-induced swelling and morphologic alterations. Herein, we unraveled AQP4 as a new therapeutic target to prevent the negative impact of METH.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder showing predominant brainstem involvement, characterized by marked slowing of rapid eye movements (saccades), particularly along the vertical plane. While the contribution of the brainstem damage for the saccadic disturbance in PSP has been extensively studied, much less is known about its cortical and subcortical pathomechanisms. We measured reflexive (prosaccades) and voluntary (antisaccades) saccades in the vertical and horizontal plane in PSP patients (n=8) and controls (n=10) in an eye tracking study, followed by the measurement of blood oxygenation-level dependent (BOLD) activation (PSP, n=6; controls, n=10) during similar saccade paradigms. Behaviorally, PSP patients evidenced slower and lower amplitude prosaccades (horizontal and vertical) and lower amplitude antisaccades (vertical) than controls. Functionally, patients showed decreased frontostriatal BOLD activation during prosaccades (horizontal and vertical) and antisaccades (vertical), relative to controls. Additionally, PSP patients showed less default mode network (DMN) deactivation than controls for all types of saccades. Within groups, controls showed no BOLD differences between horizontal and vertical prosaccades while PSP patients demonstrated greater DMN deactivation during vertical prosaccades. Both groups evidenced greater DMN deactivation during vertical antisaccades when compared to their horizontal counterpart and patients further showed relative frontostriatal BOLD hypoactivity during vertical antisaccades. We found fMRI evidence of frontostriatal hypoactivity in PSP patients relative to controls, especially during vertical saccades. These new findings highlight the impact of cortical impairment in saccadic disturbance of PSP.

Rodents’ behavioural analysis can be influenced by several factors, including housing. The PhenoWorld (PhW) is an enriched housing and testing paradigm, which proved to be relevant for screening depressive-like behaviours in rats, being remarkably sensitive for hedonic behaviour. Herein, we assessed neuronal plasticity as a consequence of living in the PhW, by comparing the structure of the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc), two brain areas involved in the circuitry regulating motivation and reward. Our findings indicate that male rats living in the PhW display increased mPFC layer II volumes, as well as increased immature spine densities and total numbers in the mPFC pyramidal neurons. The NAc volumes and NAc medium spiny neurons branching tend also to be higher in animals experiencing the physical enrichment provided in the PhW, but significant differences were not found between animals living in PhW compared to animals living in standard cages (STD6). These results demonstrate that living in a more naturalistic complex environment, closer to real life experience, impacts on the structure of brain regions implicated in complex multidimensional disorders.

Background The success of translational research depends on how well animal models mimic the pathophysiology of the human phenotype, and on the identification of disease mechanisms such as enhanced glycation. Methods Here, we studied cardiac MRI and metabolic phenotypes in human type 2 diabetes (N = 106; 55 patients+51 controls) and animal models with distinct levels of fat diet and end glycation products, to model the role of these factors in the cardiac phenotype. We included four groups of rats, designed to evaluate the role of lipid load and glucotoxicity in cardiac function and to correlate these with the cardiac phenotype observed in humans. We also aimed to assess into which extent phenotypes were related to specific risk factors. Results Stroke Volume (SV) and Peak Filling Rate (PFR) measures were similarly discriminative both in humans and animal models, particularly when enhanced glycation was present. Factorial analysis showed that reduction of multidimensionality into common main explanatory factors, in humans and animals, revealed components that equally explained the variance of cardiac phenotypes (87.62% and 83.75%, respectively). One of the components included, both in humans and animals, SV, PFR and peak ejection rate (PER). The other components included in both humans and animals are the following: ESV (end systolic volume), left ventricular mass (LVM) and ejection fraction (EF). These components were useful for between group discrimination. Conclusions We conclude that animal models of enhanced glycation and human type 2 diabetes share a striking similarity of cardiac phenotypic components and relation with metabolic changes, independently of fact content in the diet, which reinforces the role of glucose dysmetabolism in left ventricular dysfunction and provides a potentially useful approach for translational research in diabetes, in particular when testing new therapies early on during the natural history of this condition.

Recent studies have shown that programmers' cognitive load during typical code development activities can be assessed using wearable and low intrusive devices that capture peripheral physiological responses driven by the autonomic nervous system. In particular, measures such as heart rate variability (HRV) and pupillography can be acquired by nonintrusive devices and provide accurate indication of programmers' cognitive load and attention level in code related tasks, which are known elements of human error that potentially lead to software faults. This paper presents an experimental study designed to evaluate the possibility of using HRV and pupillography together with eye tracking to identify and annotate specific code lines (or even finer grain lexical tokens) of the program under development (or under inspection) with information on the cognitive load of the programmer while dealing with such lines of code. The experimental data is discussed in the paper to assess different alternatives for using code annotations representing programmers' cognitive load while producing or reading code. In particular, we propose the use of biofeedback code highlighting techniques to provide online programmer's warnings for potentially problematic code lines that may need a second look at (to remove possible bugs), and biofeedback-driven software testing to optimize testing effort, focusing the tests on code areas with higher bug probability

The study of the physiological effects underlying brain response to transcranial magnetic stimulation is important to understand its impact on neurorehabilitation. We aim to analyze the impact of a transcranial magnetic stimulation protocol, the continuous theta burst (cTBS), on human neurophysiology, particularly on contralateral motor rhythms. cTBS was applied in 20 subjects over the primary motor cortex. We recorded brain electrical activity pre- and post-cTBS with electroencephalography both at rest and while performing motor tasks, to evaluate changes in brain oscillatory patterns such as mu and beta rhythms. Moreover, we measured motor-evoked potentials before and after cTBS to assess its impact on brain's excitability. On the hemisphere contralateral to the protocol, we did observe a significant increase in mu (p = 0.027) and beta (p = 0.006) rhythms from pre- to post-cTBS, at the beginning of arm elevation. The topology of action planning and motor execution suggests that cTBS produced an inhibitory effect that propagated to the contralateral hemisphere, thereby precluding the expected/desired excitation for therapy purposes. This novel approach provides support for the notion that this protocol induces inhibitory changes in contralateral motor rhythms, by decreasing desynchronization, contradicting the ipsilateral inhibition vs. contralateral disinhibition hypothesis. Our results have implications for personalized cTBS usage as a rehabilitation intervention, suggesting that an unexpected propagation of inhibition can occur.

This study aims to investigate the relationship between structural changes in the retina and white matter in the brain, in early Alzheimer's disease (AD). Twenty-three healthy controls (mean age = 63.4±7.5 years) and seventeen AD patients (mean age = 66.5±6.6 years) were recruited for this study. By combining two imaging techniques-optical coherence tomography and diffusion tensor imaging (DTI)-the association between changes in the thickness of individual retinal layers and white matter dysfunction in early AD was assessed. Retinal layers were segmented, and thickness measurements were obtained for each layer. DTI images were analyzed with a quantitative data-driven approach to evaluating whole-brain diffusion metrics, using tract-based spatial statistics. Diffusion metrics, such as fractional anisotropy, are markers for white matter integrity. Multivariate and partial correlation analyses evaluating the association between individual retinal layers thickness and diffusion metrics were performed. We found that axial diffusivity, indexing axonal integrity, was significantly reduced in AD (p = 0.016, Cohen's d = 1.004) while in the retina, only a marginal trend for significance was found for the outer plexiform layer (p = 0.084, Cohen's d = 0.688). Furthermore, a positive association was found in the AD group between fractional anisotropy and the inner nuclear layer thickness (p < 0.05, r = 0.419, corrected for multiple comparisons by controlling family-wise error rate). Our findings suggest that axonal damage in the brain dominates early on in this condition and shows an association with retinal structural integrity already at initial stages of AD. These findings are consistent with an early axonal degeneration mechanism in AD.

This paper provides a study using Electroencephalography (EEG) to investigate the brain activity during code comprehension tasks. Three different code complexity levels according to five complexity metrics were considered. The use of EEG for this purpose is relevant, since the existing studies were mostly focused on neuroimaging techniques. Using Leave-One-Subject-Out cross-validation procedure for 30 subjects, it was found that the features related with the Gamma activity were the most common in all the folds. Regarding the brain regions, right parietal was the most frequent region contributing with more features. A Linear Discriminant Analysis Classifier for task classification, obtained a F-Measure of 92.71% for Code complexity easy, 52.25% for Code complexity intermediate and 53.13% for Code complexity advanced, revealing an evidence of mental effort saturation with the code complexity degree. This suggests that current code complexity metrics do not capture cognitive load and might not be the best approach to assess bug risk.

Our research explores a recent paradigm called Biofeedback Augmented Software Engineering (BASE) that introduces a strong new element in the software development process: the programmers' biofeedback. In this Practical Experience Report we present the results of an experiment to evaluate the possibility of using pupillography to gather biofeedback from the programmers. The idea is to use pupillography to get meta information about the programmers' cognitive and emotional states (stress, attention, mental effort level, cognitive overload,...) during code development to identify conditions that may precipitate programmers making bugs or bugs escaping human attention, and tag the corresponding code locations in the software under development to provide online warnings to the programmer or identify code snippets that will need more intensive testing. The experiments evaluate the use of pupillography as cognitive load predictor, compare the results with the mental effort perceived by programmers using NASATLX, and discuss different possibilities for the use of pupillography as biofeedback sensor in real software development scenarios.

This paper presents emergent experimental results showing that mental effort of programmers in code understanding tasks can be monitored through HRV (heart rate variability) using non-intrusive wearable devices. Results suggest that HRV is a good predictor for cognitive load when analyzing code and HRV results are consistent with the mental effort perceived by programmers using NASA-TLX. Furthermore, code complexity metrics do not correlate entirely with mental effort and do not seem a good indicator of the subjective perception of complexity felt by programmers. These first results are presented in the context of the project BASE-Biofeedback Augmented Software Engineering, which is briefly sketched, and proposes a radical neuroscience enabled approach to introduce biofeedback in software development.

The understanding of the natural history of Alzheimer’s disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Molecular characterization evaluated hippocampal levels of amyloid β (Aβ) and hyperphosphorylated tau. Magnetic resonance imaging (MRI) included assessment of hippocampal structural integrity, blood–brain barrier (BBB) permeability and neurospectroscopy to determine levels of the endogenous neuroprotector taurine. Longitudinal brain amyloid accumulation was assessed using 11C Pittsburgh compound B positron emission tomography (PET), and neuroinflammation/microglia activation was investigated using 11C-PK1195. We found altered locomotor activity at months 4/8 and 16 months and recognition memory impairment at all time points. Substantial early reduction of hippocampal volume started at month 4 and progressed over 8/12 and 16 months. Hippocampal taurine levels were significantly decreased in the hippocampus at months 4/8 and 16. No differences were found for amyloid and neuroinflammation with PET, and BBB was disrupted only at month 16. In summary, 3xTg-AD mice showed exploratory and recognition memory impairments, early hippocampal structural loss, increased Aβ and hyperphosphorylated tau and decreased levels of taurine. In sum, the 3xTg-AD animal model mimics pathological and neurobehavioral features of AD, with early-onset recognition memory loss and MRI-documented hippocampal damage. The early-onset profile suggests temporal windows and opportunities for therapeutic intervention, targeting endogenous neuroprotectors such as taurine.

Saccadic behaviour ranges from reflexive (e.g., prosaccade) to goal oriented voluntary movements (e.g., antisaccade). Behavioural asymmetries between vertical and horizontal saccades have been described both in normal individuals (greater delay of vertical prosaccades) and in disease states such as Parkinson's disease (PD) (prosaccades are short and antisaccades are delayed, especially in the vertical plane, possibly due to a frontostriatal deficit). Importantly, the cortical mechanisms for the generation of vertical saccades are largely unknown, both in health and disease, when compared with their horizontal counterpart. Moreover, studies exploring saccadic neural correlates and putative compensatory mechanisms at a functional level in PD are scarce. We investigated horizontal and vertical prosaccades and antisaccades in an eye tracking paradigm in 19 PD patients off medication and 22 healthy controls, followed by a block-design functional Magnetic Resonance Imaging (fMRI) study, consisting of two runs (prosaccade, antisaccade) of 6 blocks each (3 vertical, 3 horizontal). While saccade metrics were not significantly different between groups, PD showed left frontal underactivation during horizontal prosaccades and right parietal overactivation during horizontal and vertical prosaccades and horizontal antisaccades. Moreover, controls showed greater deactivation of the default-mode network (DMN) during antisaccades. Vertical prosaccades were associated with greater right frontal and cerebellar activity in controls, and cuneus hypoactivity in PD. Vertical antisaccades were associated with greater DMN deactivation in both groups and left frontal hypoactivity in PD. Putative functional compensatory changes in the right parietal cortex in PD patients may help to keep saccadic behaviour at the same level as the healthy controls. We provide first time evidence showing that functional cortical asymmetries between vertical and horizontal saccades occur distinctively in PD patients and healthy controls.

Objective fMRI-based neurofeedback (NF) interventions represent the method of choice for the neuromodulation of localized brain areas. Although we have already validated an fMRI-NF protocol targeting the facial expressions processing network (FEPN), its dissemination is hampered by the economical and logistical constraints of fMRI-NF interventions, which may be however surpassed by transferring it to EEG setups, due to their low cost and portability. One of the major challenges of this procedure is then to reconstruct the BOLD-fMRI signal measured at the FEPN using only EEG signals. Because these types of approaches have been poorly explored so far, here we systematically investigated the extent at which the BOLD-fMRI signal recorded from the FEPN during a fMRI-NF protocol could be reconstructed from the simultaneously recorded EEG signal. Approach Several features from both scalp and source spaces (the latter estimated using continuous EEG source imaging) were extracted and used as predictors in a regression problem using random forests. Furthermore, three different approaches to deal with the hemodynamic delay of the BOLD signal were tested. The resulting models were compared with the only approach already proposed in the literature that uses spectral features and considers different time delays. Main results The combination of linear and non-linear features (particularly the largest Lyapunov exponent and entropy measures) projected into the source space, spatially filtered by independent component analysis (ICA) and convolved with multiple HRF functions peaking at different latencies, increases significantly the reconstruction accuracy (defined as the correlation between the measured and approximated BOLD signal) from 20% (direct comparison with the method used in the current literature) to 56%. Significance With this pipeline, a more accurate reconstruction of the BOLD signal can be obtained, which will positively impact the transfer of fMRI-based neurofeedback interventions to EEG setups, and more importantly, their dissemination and efficacy in modulating the activity of the desired brain areas.

Objective Electroencephalographic biomarkers have been widely investigated in autism, in the search for diagnostic, prognostic and therapeutic outcome measures. Here we took advantage of the information available in temporal oscillatory patterns evoked by simple perceptual decisions to investigate whether stimulus dependent oscillatory signatures can be used as potential biomarkers in autism spectrum disorder (ASD). Methods We studied an extensive set of stimuli (9 categories of faces) and performed data driven classification (Support vector machine, SVM) of ASD vs. Controls with features based on the EEG power responses. We carried out an extensive time-frequency and synchrony analysis of distinct face categories requiring different processing mechanisms in terms of non-holistic vs. holistic processing. Results We found that the neuronal oscillatory responses of low gamma frequency band, locked to photographic and abstract two-tone (Mooney) face stimulus presentation are decreased in ASD vs. the control group. We also found decreased time-frequency (TF) responses in the beta band in ASD after 350 ms, possibly related to motor preparation. On the other hand, synchrony in the 30–45 Hz band showed a distinct spatial pattern in ASD. These power changes enabled accurate classification of ASD with an SVM approach. SVM accuracy was approximately 85%. ROC curves showed about 94% AUC (area under the curve). Combination of Mooney and Photographic face stimuli evoked features enabled a better separation between groups, reaching an AUC of 98.6%. Conclusion We identified a relative decrease in EEG responses to face stimuli in ASD in the beta (15–30 Hz; >350 ms) and gamma (30–45 Hz; 55–80 Hz; 50–350 ms) frequency ranges. These can be used as input of a machine learning approach to separate between groups with high accuracy. Significance Future studies can use EEG time-frequency patterns evoked by particular types of faces as a diagnostic biomarker and potentially as outcome measures in therapeutic trials.

Positron emission tomography (PET) neuroimaging with the Pittsburgh Compound_B (PiB) is widely used to assess amyloid plaque burden. Standard quantification approaches normalize PiB-PET by mean cerebellar gray matter uptake. Previous studies suggested similar pons and white-matter uptake in Alzheimer's disease (AD) and healthy controls (HC), but lack exhaustive comparison of normalization across the three regions, with data-driven diagnostic classification. We aimed to compare the impact of distinct reference regions in normalization, measured by data-driven statistical analysis, and correlation with cerebrospinal fluid (CSF) amyloid β (Aβ) species concentrations. 243 individuals with clinical diagnosis of AD, HC, mild cognitive impairment (MCI) and other dementias, from the Biomarkers for Alzheimer's/Parkinson's Disease (BIOMARKAPD) initiative were included. PiB-PET images and CSF concentrations of Aβ38, Aβ40 and Aβ42 were submitted to classification using support vector machines. Voxel-wise group differences and correlations between normalized PiB-PET images and CSF Aβ concentrations were calculated. Normalization by cerebellar gray matter and pons yielded identical classification accuracy of AD (accuracy-96%, sensitivity-96%, specificity-95%), and significantly higher than Aβ concentrations (best accuracy 91%). Normalization by the white-matter showed decreased extent of statistically significant multivoxel patterns and was the only method not outperforming CSF biomarkers, suggesting statistical inferiority. Aβ38 and Aβ40 correlated negatively with PiB-PET images normalized by the white-matter, corroborating previous observations of correlations with non-AD-specific subcortical changes in white-matter. In general, when using the pons as reference region, higher voxel-wise group differences and stronger correlation with Aβ42, the Aβ42/Aβ40 or Aβ42/Aβ38 ratios were found compared to normalization based on cerebellar gray matter., Highlights • Direct multivariate comparison of distinct reference regions in normalization of PET amyloid markers • Using the pons as ROI, higher voxel-wise group differences emerge • Using the pons as ROIs stronger correlation with Aβ42, the Aβ42/Aβ40 or Aβ42/Aβ38 ratios were found. • Evidence for statistical inferiority of CSF biomarkers • Aβ38 and Aβ40 correlated negatively with PiB-PET white-matter normalized images.

The relationship between EEG and fMRI data is poorly covered in the literature. Extensive work has been conducted in resting-state and epileptic activity, highlighting a negative correlation between the alpha power band of the EEG and the BOLD activity in the default-mode-network. The identification of an appropriate task-specific relationship between fMRI and EEG data for predefined regions-of-interest, would allow the transfer of interventional paradigms (such as BOLD-based neurofeedback sessions) from fMRI to EEG, enhancing its application range by lowering its costs and improving its flexibility. In this study, we present an analysis of the correlation between task-specific alpha band fluctuations and BOLD activity in the facial expressions processing network. We characterized the network ROIs through a stringent localizer and identified two clusters on the scalp (one frontal, one parietal-occipital) with marked alpha fluctuations, related to the task. We then check whether such power variations throughout the time correlate with the BOLD activity in the network. Our results show statistically significant negative correlations between the alpha power in both clusters and for all the ROIs of the network. The correlation levels have still not met the requirements for transferring the protocol to an EEG setup, but they pave the way towards a better understand on how frontal and parietal-occipital alpha relates to the activity of the facial expressions processing network.

Type-2 diabetes mellitus (T2DM) is a metabolic disorder with a broad range of complications in the brain that depend on the conditions that precede its onset, such as obesity and metabolic syndromes. It has been suggested that neurotransmitter and metabolic perturbations may emerge even before the early stages of T2DM and that high-caloric intake could adversely influence the brain in such states. Notwithstanding, evidence for neurochemical and structural alterations in these conditions are still sparse and controversial.To evaluate the influence of high-fat diet in the neurochemical profile and structural integrity of the rodent brain.Prospective.Wistar rats (n = 12/group).A PRESS, ISIS, RARE, and EPI sequences were performed at 9.4T.Neurochemical and structural parameters were assessed by magnetic resonance spectroscopy, voxel-based morphometry, volumetry, and diffusion tensor imaging.Measurements were compared through Student and Mann-Whitney tests. Pearson correlation was used to assess relationships between parameters.Animals submitted to high-caloric intake gained weight (P = 0.003) and developed glucose intolerance (P 0.001) but not hyperglycemia. In the hippocampus, the diet induced perturbations in glutamatergic metabolites reflected by increased levels of glutamine (P = 0.016) and glutamatergic pool (Glx) (P = 0.036), which were negatively correlated with glucose intolerance (glutamine, r = -0.804, P = 0.029), suggesting a link with neurometabolic dysregulation. At caudate-putamen, high-fat diet led to a surprising increase in the pool of N-acetylaspartate (P = 0.028). A relation with metabolic changes was again suggested by the negative correlation between glucose intolerance and levels of glutamatergic metabolites in this region (glutamate, r = -0.845, P = 0.014; Glx, r = -0.834, P = 0.020). Neither changes in phosphate compounds nor major structural alterations were observed for both regions.We found evidence that high-fat diet-induced obesity leads to distinct early and region-specific metabolic/neurochemical imbalances in the presence of early glucose intolerance even when structural alterations or T2DM are absent.1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.

High-frequency activity (HFA) is believed to subserve a functional role in cognition, but these patterns are often not accessible to scalp EEG recordings. Intracranial studies provide a unique opportunity to link the all-encompassing range of high-frequency patterns with holistic perception. We tested whether the functional topography of HFAs (up to 250Hz) is related to perceptual decision-making. Human intracortical data were recorded (6 subjects; >250channels) during an ambiguous object-recognition task. We found a spatial topography of HFAs reflecting processing anterior dorsal and ventral streams, linked to decision independently of the type of processed object/stimulus category. Three distinct regional fingerprints could be identified, with lower gamma frequency patterns (

It remains an outstanding question whether gamma‐band oscillations reflect unitary cognitive processes within the same task. EEG/MEG studies do lack the resolution or coverage to address the highly debated question whether single gamma activity patterns are linked with multiple cognitive modules or alternatively each pattern associates with a specific cognitive module, within the same coherent perceptual task. One way to disentangle these issues would be to provide direct identification of their sources, by combining different techniques. Here, we directly examined these questions by performing simultaneous EEG/fMRI using an ambiguous perception paradigm requiring holistic integration. We found that distinct gamma frequency sub‐bands reflect different neural substrates and cognitive mechanisms when comparing object perception states vs. no categorical perception. A low gamma sub‐band (near 40 Hz) activity was tightly related to the decision making network, and in particular the anterior insula. A high gamma sub‐band (∼60 Hz) could be linked to early visual processing regions. The demonstration of a clear functional topography for distinct gamma sub‐bands within the same task shows that distinct gamma‐band modulations underlie sensory processing and perceptual decision mechanisms. Hum Brain Mapp 35:5219–5235, 2014. 2014 Wiley Periodicals, Inc.

Localized neurodevelopmental defects provide an opportunity to study structure-function correlations in the human nervous system. This unique multimodal case report of epileptogenic dysplasia in the visual cortex allowed exploring visual function across distinct pathways in retinotopic regions and the dorsal stream, in relation to fMRI retinotopic mapping and spike triggered BOLD responses. Pre-surgical EEG/video monitoring, MRI/DTI, EEG/fMRI, PET and SPECT were performed to characterize structure/function correlations in this patient with a very early lesion onset. In addition, we included psychophysical methods (assessing parvo/konio and magnocellular pathways) and retinotopic mapping. We could identify dorsal stream impairment (with extended contrast sensitivity deficits within the input magno system contrasting with more confined parvocellular deficits) with disrupted active visual field input representations in regions neighboring the lesion. Simultaneous EEG/fMRI identified perilesional and retinotopic bilaterally symmetric BOLD deactivation triggered by interictal spikes, which matched the contralateral spread of magnocellular dysfunction revealed in the psychophysical tests. Topographic changes in retinotopic organization further suggested long term functional effects of abnormal electrical discharges during brain development. We conclude that fMRI based visual field cortical mapping shows evidence for retinotopic dissociation between magno and parvocellular function well beyond striate cortex, identifiable in high level dorsal visual representations around visual area V3A which is consistent with the effects of epileptic spike triggered negative BOLD.

The identification and interpretation of facial expressions is an important feature of social cognition. This characteristic is often impaired in various neurodevelopmental disorders. Recent therapeutic approaches to intervene in social communication impairments include neurofeedback (NF). In this study, we present a NF real-time functional Magnetic Resonance Imaging (rt-fMRI), combined with electroencephalography (EEG) to train social communication skills. In this sense, we defined the right Superior Temporal Sulcus as our target region-of-interest. To analyze the correlation between the fMRI regions of interest and the EEG data, we transposed the sources located at the nearest cortical location to the target region. We extracted a set of 75 features from EEG segments and performed a correlation analysis with the brain activations extracted from rt-fMRI in the right pSTS region. The finding of significant correlations of simultaneously measured signals in distinct modalities (EEG and fMRI) is promising. Future studies should address whether the observed correlation levels between local brain activity and scalp measures are sufficient to implement NF approaches.

Saccadic intrusions are involuntary saccades that interrupt fixation and are usually conjugate between eyes.1 Although saccadic intrusions may be seen in healthy individuals, they also accompany certain neurologic disorders (usually manifesting higher frequency or amplitude) including cerebellar disease.2 We present a patient with spinocerebellar ataxia type 3 (SCA3) with an uncommon monocular/disconjugate alternating type of saccadic intrusion.

Human interaction and physical environmental factors are part of the stimuli presented to laboratory animals everyday, influencing their behaviour and physiology and contributing to their welfare. Certain environmental conditions and routine procedures in the animal facility might induce stress responses and when the animal is unable to maintain its homeostasis in the presence of a particular stressor, the animal's wellbeing is threatened. This review article summarizes several published studies on the impact of environmental factors such as light, noise, cage cleaning and in-house transport on welfare and stress of laboratory rats. The behaviour and physiological responses of laboratory rats to different environmental housing conditions and routine procedures are reviewed. Recommendations on the welfare of laboratory rats and refinements in experimental design are discussed and how these can influence and improve the quality of scientific data.

Tese de Doutoramento em Ciências da Saúde, Animal models play a central role in biomedical sciences having an important role in the progress of knowledge regarding the pathophysiology of neuropsychiatric disorders, as well as in the development of treatment strategies and testing new drugs for human application. One of the more prevalent neuropsychiatric disorders, causing serious medical and social problems, is depression. The full aetiology of this multidimensional and heterogeneous disorder, as well as its neurobiology, are not yet understood, and the diagnosis of depression in itself is based on multiple symptoms or psychopathological phenomena that together characterize a depressive state. Furthermore, the efficacy of antidepressive treatments is not always similar for different patients and the neurobiological mechanisms of action of commonly used antidepressant drugs are also not yet fully understood. The need to further investigate the psychopathology of the disorder and the mechanisms underlying the actions of antidepressant drugs and treatments, and the recognition that there are many fundamental physiological and behavioural responses that have been evolutionarily conserved between species, depending on similar neural structures and circuits, has resulted in scientists developing and validating several approaches to study depression. These include mimicking the disorder in animal model systems and using several tests to screen for the “symptoms” or depressive-like behaviours. Still, these models and tests present several limitations and their poor predictive power has been argued to be one of the reasons for the lack of efficacy of antidepressant drugs in humans. In face of the drawbacks and limitations presented by test paradigms in use in the field of behavioural neuroscience, and recognizing the need to improve those paradigms for the progress in the knowledge of the pathophysiology and therapeutics of mood disorders, we developed and validated a new paradigm for testing and analysing behavioural data – the “PhenoWorld” (PhW). This new paradigm is a refined housing setup, where groups of 6 rats with implanted RFID transponders live in an ethological enriched setting and have their feeding, locomotor activity, resting and social behavior automatically monitored. In a first study, we assessed the face and predictive validity of our new paradigm using a battery of emotional and cognitive standard tests in order to characterize the behavioral phenotype of animals living in the PhW and in standard conditions (in groups of 6 and 2 rats), after exposure to an unpredictable chronic mild stress (uCMS), and after exposure to uCMS and antidepressant (fluoxetine) treatment. We have shown that animals living in the PhW displayed similar, but more striking, behavioral differences when exposed to uCMS, such as increased behavioral despair shown in the forced swimming test, resting/sleep behaviour disturbances and reduced social interactions, compared to standard housed animals. Moreover, several PhW-cage behaviors, such as spontaneous will to feed or to exercise in running wheels, proved to be sensitive indicators of depressive-like behavior. In a second study, we assessed neuronal plasticity as a consequence of living in the PhW in a group of 6 animals, by comparing the structure of the prefrontal cortex (PFC) and the nucleus accumbens (NAc), two brain areas involved in the circuitry regulating motivation and reward, of PhW animals compared to those housed in standard conditions in social groups of 6 (STD6) and 2 rats (STD2). Findings indicated that rats living in the PhW displayed increased medial PFC layer II volumes, increased branching and length, as well as increased spine densities and spine numbers per neuron, in medial PFC pyramidal neurons. In the NAc, significant increases were only found for the length of NAc shell medium spiny neurons. The results proved the construct validity of the PhW and revealed that living in a naturalistic complex environment, closer to ‘real life experience’, impacts on the structure of brain regions implicated in complex multidimensional disorders. Finally, we addressed the animal welfare comparing the three housing conditions: PhW, STD6 and STD2. In this study, home-cage behaviour analysis showed that PhW animals have a clearer circadian pattern of sleep and social interactions. By promoting a good basic health and functioning, and the performance of natural behaviours with controllability but still keeping some physical and social challenges, the PhW stimulates positive affective states and higher motivation in rats. Even though understanding animal welfare has always some degree of subjectivity, these are evidences pointing for an increased welfare of animals living in the PhW. In conclusion, after validating the PhW to study a multidimensional mood disorder, we believe this new paradigm and naturalistic housing setting allows to address real systems neuroscience and can be very useful in future animal studies of other complex emotional and cognitive disorders., Os modelos animais têm um papel preponderante nas ciências biomédicas contribuindo para o progresso no conhecimento da patofisiologia das doenças neuropsiquiátricas e para o desenvolvimento de estratégias de tratamento, bem como para testar novos medicamentos em ensaios pré-clínicos. Uma das doenças psiquiátricas mais prevalentes, caracteristicamente multidimensional e heterogénea e que causa graves problemas médicos e sociais, é a depressão. Nem a etiologia, nem a neurobiologia desta doença são ainda completamente conhecidas e o diagnóstico de depressão é feito com base em múltiplos sintomas ou fenómenos psicopatológicos que no seu conjunto caracterizam o estado depressivo. A eficácia dos tratamentos antidepressivos não é semelhante para todos os pacientes, e os mecanismos neurobiológicas de ação dos tratamentos e fármacos antidepressivos não são ainda totalmente conhecidos. A necessidade de continuar a investigar a psicopatologia da depressão e os mecanismos pelos quais os antidepressivos exercem os seus efeitos, bem como o reconhecimento de que existem muitas respostas fisiológicas e comportamentais evolucionariamente conservadas entre espécies, levou os cientistas a desenvolver e validar estratégias de estudo da depressão mimetizando a doença em modelos animais e usando diversos testes para avaliar comportamentos tipo depressivos ou “sintomas”. No entanto, os testes animais desenvolvidos apresentam diversas limitações e um poder preditivo baixo, contribuindo para a baixa eficácia dos fármacos antidepressivos em humanos. Tendo em conta todas as limitações apresentadas e reconhecendo a necessidade de melhorar os paradigmas de comportamento animal usados em neurociências no sentido de promover o progresso no conhecimento da patofisiologia e terapêutica das doenças emocionais, desenvolvemos e validamos um novo paradigma para testar e analisar dados comportamentais de ratos – o “PhenpoWorld” (PhW). Este novo paradigma providencia um sistema de alojamento melhorado onde grupos de 6 ratos, com um microship emissor de radiofrequência implantado subcutaneamente, vivem num ambiente etologicamente mais rico e onde têm os seus comportamentos alimentares, atividade locomotora, e comportamento social automaticamente monitorizado. No primeiro estudo realizado, avaliamos as validades aparente e preditiva do novo paradigma utilizando uma bateria de testes de comportamento emocional e cognitivo de forma a caracterizar o fenótipo dos animais a viver no PhW ou em gaiolas convencionais (em grupos de 6 ou de 2 ratos), após exposição crónica a stress ( uCMS) ou após exposição a uCMS e tratamento com fluoxetina. Os resultados obtidos mostraram que os animais que vivem no PhW apresentam diferenças comportamentais semelhantes, mas mais vincadas, quando expostos a stress, tais como distúrbios do padrão de sono/descanso e redução da frequência de interações sociais. Além disso, verificamos que vários comportamentos apenas possíveis no PhW (vontade espontânea de atravessar portas automáticas para ir comer e ir fazer exercício nas rodas) são indicadores sensíveis de comportamento tipo depressivo. No segundo estudo, avaliamos a plasticidade neuronal como consequência de viver no PhW num grupo de 6 animais, comparando a estrutura do córtex pré-frontal ( PFC) e do nuccleus accumbens ( NAc), duas áreas do cérebro envolvidas nos circuitos que regulam motivação e recompensa, entre esses animais e animais alojados em gaiolas convencionais em grupos de 6 (STD6) e de 2 ratos (STD2). Os resultados revelaram, por exemplo, que os ratos que vivem no PhW apresentam um aumento do volume da camada II do PFC medial, e um aumento da complexidade das dendrites e do nº de espinhas por neurónio nos neurónios piramidais da camada II-III do PFC medial. No NAc, apenas verificamos aumentos significativos no comprimento das dendrites dos neurónios espinhosos médios da subdivisão NAc shell. Estes resultados refletem a validade construtiva do PhW e revelam que viver nesse ambiente naturalístico complexo, mais parecido com a vida real, tem impacto nas áreas do cérebro implicadas nas doenças multidimensionais complexas. Finalmente, avaliamos o bem-estar animal comparando as três condições de alojamento (PhW, STD6 e STD2) e mostramos que os padrões circadianos de sono e das interações sociais são mais marcados no PhW. A promoção da saúde, e o estímulo de comportamentos naturais com controlabilidade mas mantendo alguns desafios físicos e sociais contribuem para um estado afetivo positivo dos animais no PhW e para a sua elevada motivação e são indicadores de elevado bem-estar animal. Em conclusão, após validação do PhW no estudo de um modelo de depressão, acreditamos que este novo paradigma e gaiola naturalista permita futuros estudos no âmbito das neurociências de sistemas tornando-se muito útil em estudos animais de outras doenças emocionais e cognitivas complexas.

It has been hypothesized that neural synchrony underlies perceptual coherence. The hypothesis of loss of central perceptual coherence has been proposed to be at the origin of abnormal cognition in autism spectrum disorders and Williams syndrome, a neurodevelopmental disorder linked with autism, and a clearcut model for impaired central coherence. We took advantage of this model of impaired holistic processing to test the hypothesis that loss of neural synchrony plays a separable role in visual integration using EEG and a set of experimental tasks requiring coherent integration of local elements leading to 3-D face perception. A profound reorganization of brain activity was identified. Neural synchrony was reduced across stimulus conditions, and this was associated with increased amplitude modulation at 25–45 Hz. This combination of a dramatic loss of synchrony despite increased oscillatory activity is strong evidence that synchrony underlies central coherence. This is the first time, to our knowledge, that dissociation between amplitude and synchrony is reported in a human model of impaired perceptual coherence, suggesting that loss of phase coherence is more directly related to disruption of holistic perception.

An exciting area in cognitive neuroscience concerns the investigation of neural mechanisms underlying the emergence of visual perceptual representations. Multistable interpretations of the visual world are striking phenomena that may occur when the retinal image is compatible with multiple perceptual solutions. This occurs even when the physical pattern of retinal stimulation remains constant. Perceptual decision making is thus defined by the choice of an interpretation among a set of potentially ambiguous alternatives based on peripheral sensory evidence. We discuss current multimodal approaches to investigate the neural correlates of competition between multistable alternative neural representations and the generation of antagonistic perceptual interpretations.

In tissue engineering, the evaluation of the host response to the biomaterial implantation must be assessed to determine the extent of the inflammatory reaction. We studied the degradation of poly(butylene succinate) and chitosan in vitro using lipase and lysozyme enzymes, respectively. The subcutaneous implantation of the scaffolds was performed to assess tissue response. The type of inflammatory cells present in the surrounding tissue, as well as within the scaffold, was determined histologically and by immunohistochemistry. In the presence of lipase or lysozyme, the water uptake of the scaffolds increased. Based on the weight loss data and scanning electron microscopy analysis, the lysozyme combined with lipase had a notable effect on the in vitro degradation of the scaffolds. The in vivo implantation showed a normal inflammatory response, with presence of neutrophils, in a first stage, and macrophages, lymphocytes, and giant cells in a later stage. Vascularization in the surrounding tissue and within the implant increased with time. Moreover, the collagen deposition increased with time inside the implant. In vivo, the scaffolds maintained the structural integrity. The degradation in vitro was faster and greater compared to that observed in vivo within the same time periods., Ana R Costa-Pinto was supported by the scholarship SFRH/24735/2005 from the Portuguese “Fundação para a Ciência e a Tecnologia” (FCT). This work was partially supported by the European Network of Excellence EXPERTISSUES (NMP3-CT-2004-500283) and FCT funded project Maxbone (PTDC/ SAU-ENB/115179/2009).

Modeling depression in animals has inherent complexities that are augmented by intrinsic difficulties to measure the characteristic features of the disorder. Herein, we describe the PhenoWorld (PhW), a new setting in which groups of six rats lived in an ethological enriched environment, and have their feeding, locomotor activity, sleeping and social behavior automatically monitored. A battery of emotional and cognitive tests was used to characterize the behavioral phenotype of animals living in the PhW and in standard conditions (in groups of six and two rats), after exposure to an unpredictable chronic mild stress paradigm (uCMS) and antidepressants. Data reveal that animals living in the PhW displayed similar, but more striking, behavioral differences when exposed to uCMS, such as increased behavioral despair shown in the forced swimming test, resting/sleep behavior disturbances and reduced social interactions. Moreover, several PhW-cage behaviors, such as spontaneous will to go for food or exercise in running wheels, proved to be sensitive indicators of depressive-like behavior. In summary, this new ethological enriched paradigm adds significant discriminative power to screen depressive-like behavior, in particularly rodent's hedonic behavior.

Williams syndrome (WS) is a clinical model of dorsal stream vulnerability and impaired visual integration. However, little is still known about the neurophysiological correlates of perceptual integration in this condition. We have used a 3D structure-from-motion (SFM) integrative task to characterize the neuronal underpinnings of 3D perception in WS and to probe whether gamma oscillatory patterns reflect changed holistic perception. Coherent faces were parametrically modulated in 3D depth (three different depth levels) to vary levels of stimulus ambiguity. We have found that the electrophysiological (EEG/ERP) correlates of such holistic percepts were distinct across groups. Independent component analysis demonstrated the presence of a novel component with a late positivity around 200 ms that was absent in controls. Source localization analysis of ERP signals showed a posterior occipital shift in WS and reduced parietal dorsal stream sources. Interestingly, low gamma-band oscillations (20-40 Hz) induced by this 3D perceptual integration task were significantly stronger and sustained during the stimulus presentation in WS whereas high gamma-band oscillations (60-90 Hz) were reduced in this clinical model of impaired visual coherence, as compared to controls. These observations suggest that dorsal stream processing of 3D SFM stimuli has distinct neural correlates in WS and different cognitive strategies are employed by these patients to reach visual coherence. Importantly, we found evidence for the presence of different sub-bands (20-40 Hz/60-90 Hz) within the gamma range which can be dissociated concerning the respective role on the coherent percept formation, both in typical and atypical development.