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Facial emotion perception can be studied from the point of view of dynamic systems whose output may depend not only on current input but also on prior history — a phenomenon known as hysteresis. In cognitive neuroscience, hysteresis has been described as positive (perceptual persistence) or negative (fatigue of current percept) depending on whether perceptual switching occurs later or earlier than actual physical stimulus changes. However, its neural correlates remain elusive. We used dynamic transitions between emotional expressions and combined behavioral assessment with functional magnetic resonance imaging (fMRI) to investigate the underlying circuitry of perceptual hysteresis in facial emotion recognition. Our findings revealed the involvement of face-selective visual areas — fusiform face area (FFA) and superior temporal sulcus (STS) — in perceptual persistence as well as the right anterior insula. Moreover, functional connectivity analyses revealed an interplay between the right anterior insula and medial prefrontal cortex, which showed to be dependent on the presence of positive hysteresis. Our results support the hypothesis that high-order regions are involved in perceptual stabilization and decision during perceptual persistence (positive hysteresis) and add evidence to the role of the anterior insula as a hub of sensory information in perceptual decision-making.

Introduction. To design more effective interventions, such as neurostimulation, for stroke rehabilitation, there is a need to understand early physiological changes that take place that may be relevant for clinical monitoring. We aimed to study changes in neurophysiology following recent ischemic stroke, both at rest and with motor planning and execution. Materials and Methods. We included 10 poststroke patients, between 7 and 10 days after stroke, and 20 age-matched controls to assess changes in cortical motor output via transcranial magnetic stimulation and in dynamics of oscillations, as recorded using electroencephalography (EEG). Results. We found significant differences in cortical oscillatory patterns comparing stroke patients with healthy participants, particularly in the beta rhythm during motor planning ( p = 0.011 ) and execution ( p = 0.004 ) of a complex movement with fingers from both hands simultaneously. Discussion. The stroke lesion induced a decrease in event-related desynchronization in patients, in comparison to controls, providing evidence for decreased disinhibition. Conclusions. After a stroke lesion, the dynamics of cortical oscillations is changed, with an increasing neural beta synchronization in the course of motor preparation and performance of complex bimanual finger tasks. The observed patterns may provide a potential functional measure that could be used to monitor and design interventional approaches in subacute stages.

Complexity is the key element of software quality. This article investigates the problem of measuring code complexity and discusses the results of a controlled experiment to compare different views and methods to measure code complexity. Participants (27 programmers) were asked to read and (try to) understand a set of programs, while the complexity of such programs is assessed through different methods and perspectives: (a) classic code complexity metrics such as McCabe and Halstead metrics, (b) cognitive complexity metrics based on scored code constructs, (c) cognitive complexity metrics from state-of-the-art tools such as SonarQube, (d) human-centered metrics relying on the direct assessment of programmers’ behavioral features (e.g., reading time, and revisits) using eye tracking, and (e) cognitive load/mental effort assessed using electroencephalography (EEG). The human-centered perspective was complemented by the subjective evaluation of participants on the mental effort required to understand the programs using the NASA Task Load Index (TLX). Additionally, the evaluation of the code complexity is measured at both the program level and, whenever possible, at the very low level of code constructs/code regions, to identify the actual code elements and the code context that may trigger a complexity surge in the programmers’ perception of code comprehension difficulty. The programmers’ cognitive load measured using EEG was used as a reference to evaluate how the different metrics can express the (human) difficulty in comprehending the code. Extensive experimental results show that popular metrics such as V(g) and the complexity metric from SonarSource tools deviate considerably from the programmers’ perception of code complexity and often do not show the expected monotonic behavior. The article summarizes the findings in a set of guidelines to improve existing code complexity metrics, particularly state-of-the-art metrics such as cognitive complexity from SonarSource tools.

Transcranial magnetic stimulation (TMS) can be useful for therapeutic purposes for a variety of clinical conditions. Numerous studies have indicated the potential of this non-invasive brain stimulation technique to recover brain function and to study physiological mechanisms. Following this line, the articles contemplated in this Research Topic show that this field of knowledge is rapidly expanding and considerable advances have been made in the last few years. There are clinical protocols already approved for Depression (and anxiety comorbid with major depressive disorder), Obsessive compulsive Disorder (OCD), migraine headache with aura, and smoking cessation treatment but many studies are concentrating their efforts on extending its application to other diseases, e.g., as a treatment adjuvant. In this Research Topic we have the example of using TMS for pain, post-stroke depression, or smoking cessation, but other diseases/injuries of the central nervous system need attention (e.g., tinnitus or the surprising epilepsy). Further, the potential of TMS in health is being explored, in particular regarding memory enhancement or the mapping of motor control regions, which might also have implications for several diseases. published

Although stroke is the main cause of brain damage worldwide, stroke therapies are based on blood reperfusion and do not target cerebral parenchyma. Ischemic stroke (representing 87% of all strokes) causes cerebral damage due to oxygen and tissue energy depletion, which lead to acidosis, inflammation, excitotoxicity and oxidative stress. Carbon monoxide (CO) is an endogenous gasotransmitter produced by heme oxygenase cleavage of the heme group. CO promotes cytoprotection by limiting inflammation and preventing cell death in several tissues including the brain. Previous studies have demonstrated the protective role of CO in the mouse ischemic stroke model, middle cerebral artery occlusion (MCAo) by histological analysis when CO is when applied before ischemia. Herein, there are two main novelties. First CO is administrated following stroke, which better mimics its potential future use as therapeutic drug. Secondly, imaging techniques were used to elucidate the effect of this gasotransmitter at the metabolic, vascular and anatomic levels.The putative neuroprotective effects of CO following MCAo were assessed by 3 i.p. injections of the CO-releasing molecule CORM-A1 (3 mg/kg), administered 6, 24 and 48h after reperfusion. Magnetic Resonance Imaging was performed 1 day and 7 days after reperfusion using T2-weighted, diffusion weighted images, proton spectroscopy (1H-MRS) and perfusion (dynamic contrast enhanced images).1H-MRS also allowed the comparison between metabolite signatures at day 1 versus 7 day following MCAo. Furthermore, CORM-A1 limited the loss of blood-brain barrier (BBB) integrity as it reduced the edema formation. Furthermore, the CO donor minimized the metabolite load loss at an early stage after MCAo, both in striatum and cortex.In conclusion and based on MRI analysis, CO has a protective role in the recovery from stroke injury, mainly by acting on BBB integrity and brain metabolism.

Software programming is a modern activity that poses strong challenges to the human brain. The neural mechanisms that support this novel cognitive faculty are still unknown. On the other hand, reading and calculation abilities represent slightly less recent human activities, in which neural correlates are relatively well understood. We hypothesize that calculus and reading brain networks provide joint underpinnings with distinctly weighted contributions which concern programming tasks, in particular concerning error identification. Based on a meta-analysis of the core regions involved in both reading and math and recent experimental evidence on the neural basis of programming tasks, we provide a theoretical account that integrates the role of these networks in program understanding. In this connectivity-based framework, error-monitoring processing regions in the frontal cortex influence the insula, which is a pivotal hub within the salience network, leading into efficient causal modulation of parietal networks involved in reading and mathematical operations. The core role of the anterior insula and anterior midcingulate cortex is illuminated by their relation to performance in error processing and novelty. The larger similarity that we observed between the networks underlying calculus and programming skills does not exclude a more limited but clear overlap with the reading network, albeit with differences in hemispheric lateralization when compared with prose reading. Future work should further elucidate whether other features of computer program understanding also use distinct weights of phylogenetically “older systems” for this recent human activity, based on the adjusting influence of fronto-insular networks. By unraveling the neural correlates of program understanding and bug detection, this work provides a framework to understand error monitoring in this novel complex faculty.

Deficits in mitochondrial function and redox deregulation have been attributed to Huntington's disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. In the present study, we analysed changes in mitochondrial function and production of reactive oxygen species (ROS) at early stages and with disease progression. Studies were performed in vivo in human brain by PET using [

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Assessing comprehension difficulties requires the ability to assess cognitive load. Changes in cognitive load induced by comprehension difficulties could be detected with an adequate time resolution using different biofeedback measures (e.g., changes in the pupil diameter). However, identifying the Spatio-temporal sources of content comprehension difficulties (i.e., when, and where exactly the difficulty occurs in content regions) with a fine granularity is a big challenge that has not been explicitly addressed in the state-of-the-art. This paper proposes and evaluates an innovative approach named Intelligent BiofeedbackAugmented Content Comprehension (TellBack) to explicitly address this challenge. The goal is to autonomously identify regions of digital content that cause user's comprehension difficulty, opening the possibility to provide real-time comprehension support to users. TellBack is based on assessing the cognitive load associated with content comprehension through non-intrusive cheap biofeedback devices that acquire measures such as pupil response or Heart Rate Variability (HRV). To identify when exactly the difficulty in comprehension occurs, physiological manifestations of the Autonomic Nervous System (ANS) such as the pupil diameter variability and the modulation of HRV are exploited, whereas the fine spatial resolution (i.e., the region of content where the user is looking at) is provided by eye-tracking. The evaluation results of this approach show an accuracy of 83.00% ± 0.75 in classifying regions of content as difficult or not difficult using Support Vector Machine (SVM), and precision, recall, and micro F1-score of 0.89, 0.79, and 0.83, respectively. Results obtained with 4 other classifiers, namely Random Forest, k-nearest neighbor, Decision Tree, and Gaussian Naive Bayes, showed a slightly lower precision. TellBack outperforms the state-of-the-art in precision & recall by 23% and 17% respectively.

Error-related electroencephalographic (EEG) signals have been widely studied concerning the human cognitive capability of differentiating between erroneous and correct actions. Midfrontal error-related negativity (ERN) and theta band oscillations are believed to underlie post-action error monitoring. However, it remains elusive how early monitoring activity is trackable and what are the pre-response brain mechanisms related to performance monitoring. Moreover, it is still unclear how task-specific parameters, such as cognitive demand or motor control, influence these processes. Here, we aimed to test pre- and post-error EEG patterns for different types of motor responses and investigate the neuronal mechanisms leading to erroneous actions. We implemented a go/no-go paradigm based on keypresses and saccades. Participants received an initial instruction about the direction of response to be given based on a facial cue and a subsequent one about the type of action to be performed based on an object cue. The paradigm was tested in 20 healthy volunteers combining EEG and eye tracking. We found significant differences in reaction time, number, and type of errors between the two actions. Saccadic responses reflected a higher number of premature responses and errors compared to the keypress ones. Nevertheless, both led to similar EEG patterns, supporting previous evidence for increased ERN amplitude and midfrontal theta power during error commission. Moreover, we found pre-error decreased theta activity independent of the type of action. Source analysis suggested different origin for such pre- and post-error neuronal patterns, matching the anterior insular cortex and the anterior cingulate cortex, respectively. This opposite pattern supports previous evidence of midfrontal theta not only as a neuronal marker of error commission but also as a predictor of action performance. Midfrontal theta, mostly associated with alert mechanisms triggering behavioral adjustments, also seems to reflect pre-response attentional mechanisms independently of the action to be performed. Our findings also add to the discussion regarding how salience network nodes interact during performance monitoring by suggesting that pre- and post-error patterns have different neuronal sources within this network.

ObjectivesWe aimed to investigate the antiepileptic effects of cathodal transcranial direct current stimulation (c-tDCS) and mechanisms of action based on its effects on the neurotransmitters responsible for the abnormal synchrony patterns seen in pharmacoresistant epilepsy. This is the first study to test the impact of neurostimulation on epileptiform interictal discharges (IEDs) and to measure brain metabolites in the epileptogenic zone (EZ) and control regions simultaneously in patients with pharmacoresistant epilepsy.MethodsThis is a hypothesis-driven pilot prospective single-blinded repeated measure design study in patients diagnosed with pharmacoresistant epilepsy of temporal lobe onset. We included seven patients who underwent two sessions of c-tDCS (sham followed by real). The real tDCS session was 20 min in duration and had a current intensity of 1.5 mA delivered via two surface electrodes that had dimensions of 3 × 4 cm. The cathode electrode was placed at FT7 in the center whereas the anode at Oz in the center. After each session, we performed electroencephalographic recording to count epileptiform IEDs over 30 min. We also performed magnetic resonance spectroscopy (MRS) to measure brain metabolite concentrations in the two areas of interest (EZ and occipital region), namely, gamma-aminobutyric acid (GABA), glutamate (Glx), and glutathione. We focused on a homogenous sample where the EZ and antiepileptic medications are shared among patients.ResultsReal tDCS decreased the number of epileptiform IEDs per min (from 9.46 ± 2.68 after sham tDCS to 5.37 ± 3.38 after real tDCS), p = 0.018, as compared to sham tDCS. GABA was decreased in the EZ after real c-tDCS stimulation as compared to sham tDCS (from 0.129 ± 0.019 to 0.096 ± 0.018, p = 0.02). The reduction in EZ GABA correlated with the reduction in the frequency of epileptiform IED per min (rho: 0.9, p = 0.003).ConclusionThese results provide a window into the antiepileptic mechanisms of action of tDCS, based on local and remote changes in GABA and neural oscillatory patterning responsible for the generation of interictal epileptiform discharges.

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

Previous studies about the modulation of the vasculature by CO were performed exclusively in male or sexually immature animals. Understanding the sex differences regarding systemic drug processing and pharmacodynamics is an important feature for safety assessment of drug dosing and efficacy. In this work, we used CORM-A1 as source of CO to examine the effects of this gasotransmitter on brain perfusion and the sex-dependent differences. Dynamic contrast-enhanced imaging (DCE)-based analysis was used to characterize the properties of CO in the modulation of cerebral vasculature in vivo, in adult C57BL/6 healthy mice. Perfusion of the temporal muscle, maxillary vein and in hippocampus, cortex and striatum was analysed for 108 min following CORM-A1 administration of 3 or 5 mg/kg. Under control conditions, brain perfusion was lower in females when compared with males. Under CO treatment, females showed a surprisingly overall reduced perfusion compared with controls (F = 3.452, p = .0004), while no major alterations (or even the expected increase) were observed in males. Cortical structures were only modulated in females. A striking female-dominated vasoconstriction effect was observed in the hippocampus and striatum following administration of CO, in this mixed-sex cohort. As these two regions are implicated in episodic and procedural memory formation, CO may have a relevant impact in learning and memory.

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.

Defects in mitochondrial function and mitochondrial-related redox deregulation have been attributed to Huntington’s disease (HD), a genetic neurodegenerative disorder largely affecting the striatum. However, whether these changes occur in early stages of the disease and can be detected in vivo is still unclear. Thus, in the present study, we analyzed changes in mitochondrial function and overreduced states associated with production of reactive oxygen species (ROS) at early stages and along disease progression. Studies were performed in vivo in human brain using positron emission tomography (PET) using [64Cu]-ATSM and ex vivo in human skin fibroblasts of premanifest and prodromal (Pre-M) and manifest HD patients; in vivo brain [64Cu]-ATSM PET and isolated mitochondria derived from striatum and cortex were also analyzed in YAC128 transgenic mouse at pre-symptomatic (3 month-old, mo) and symptomatic (6 to 12 mo) stages. Oxygen consumption rates were assessed by Seahorse analysis, hydrogen peroxide levels were determined using fluorescent probes and mitochondrial morphology by transmission electron microscopy in human skin fibroblasts and mouse striatal and cortical isolated mitochondria. Pre-M HD carriers exhibited enhanced whole-brain (with exception of caudate) [64Cu]-ATSM labelling, correlating with CAG repeat number. Fibroblasts from Pre-M showed enhanced basal and maximal respiration, proton (H+) leak and increased hydrogen peroxide levels, the later progressing to manifest HD; mitochondria from fibroblasts of Pre-M HD carriers also showed reduced roundness, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [64Cu]-ATSM in YAC128 mouse striatum. Pre-symptomatic YAC128 mouse striatal isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production, along with increased complex II and III activities; mouse HD mitochondria also showed enhanced mitochondrial hydrogen peroxide levels and roundness, as revealed by brain ultrastructure analysis, and defects in Ca2+ handling, supporting increased striatal susceptibility in YAC128 mouse brain. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter extending over manifest disease stages.

Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is the most common form of dominant SCA worldwide. Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (1H-MRS) provide promising non-invasive diagnostic and follow-up tools, also serving to evaluate therapies efficacy. However, pre-clinical studies showing relationship between MRI-MRS based biomarkers and functional performance are missing, which hampers an efficient clinical translation of therapeutics. This study assessed motor behaviour, neurochemical profiles, and morphometry of the cerebellum of MJD transgenic mice and patients aiming at establishing magnetic-resonance-based biomarkers. 1H-MRS and structural MRI measurements of MJD transgenic mice were performed with a 9.4 Tesla scanner, correlated with motor performance on rotarod and compared with data collected from human patients. We found decreased cerebellar white and grey matter and enlargement of the fourth ventricle in both MJD mice and human patients as compared to controls. N-acetylaspartate (NAA), NAA + N-acetylaspartylglutamate (NAA + NAAG), Glutamate, and Taurine, were significantly decreased in MJD mouse cerebellum regardless of age, whereas myo-Inositol (Ins) was increased at early time-points. Lower neurochemical ratios levels (NAA/Ins and NAA/total Choline), previously correlated with worse clinical status in SCAs, were also observed in MJD mice cerebella. NAA, NAA + NAAG, Glutamate, and Taurine were also positively correlated with MJD mice motor performance. Importantly, these 1H-MRS results were largely analogous to those found for MJD in human studies and in our pilot data in human patients. We have established a magnetic resonance-based biomarker approach to monitor novel therapies in preclinical studies and human clinical trials.

Day-to-day we have to make choices. Even simple decisions involve complex cognitive processes that are still not clearly understood. When it comes to critical decisions which may lead to impactful and irreversible consequences, the understanding of the decision-making process is highly relevant. Dysfunctional coping responses may lead to stress and ultimately to trauma. In the present project, we aim to understand decision-making in the context of firefighting and to study how neurocognitive control and stress management strategies affect decision-making. We present here a functional brain imaging paradigm coupled with biosensors while firefighters play a decision-making task. In this computerized task, the firefighter faces the dilemma of entering or not in a burning house, with variable risk of house collapsing, variable number of victims in danger and variable probability of the victims saving themselves. We present here the preliminary results from a cohort of 13 firefighters, of which none presented clinically significant symptoms of post-traumatic stress disorder. We found brain regions, including the ventromedial and dorsolateral prefrontal cortices and angular gyrus, showing a parametric pattern of activation during the decision phase, i.e. the lower the risk of collapsing, the higher the neural activity in these areas. This suggests that these regions are processing that risk information and signalling the chances of being successful in the rescue phase. We also found that the power in high frequencies of the pulse rate variability of this cohort of firefighters is higher when they decide to enter for the rescue. It is suggestive that deciding not to enter for rescue causes an increase in arousal, which may be related to the expectation about the victims’ outcome (whether they survived or not). Concerning coping strategies, we found that active coping used in personal context was significantly correlated with the age and the years of experience in our sample of firefighters. We aim to understand if this pattern of brain activity reflects the coping strategies and if, in turn, it is reflected in the physiological signals we measure. Concurrently, we are recruiting firefighters with post-traumatic stress disorder and non-firefighters to perform the same task. We will investigate whether the decision processes in firefighters are different from non-firefighters, and we will address if post-traumatic stress disorder impairs decision-making in this context. Biosignals will also be used in a second phase of the project to inform training systems about the physiological state of the firefighter during virtual reality simulation. This may help developing optimal neurocognitive control and better coping strategies to deal with stress.

Objectives: Transcranial magnetic stimulation, in particular continuous theta burst (cTBS), has been proposed for stroke rehabilitation, based on the concept that inhibition of the healthy hemisphere helps promote the recovery of the lesioned one. We aimed to study its effects on cortical excitability, oscillatory patterns, and motor function, the main aim being to identify potentially beneficial neurophysiological effects.Materials and Methods: We applied randomized real or placebo stimulation over the unaffected primary motor cortex of 10 subacute (7 ± 3 days) post-stroke patients. Neurophysiological measurements were performed using electroencephalography and electromyography. Motor function was assessed with the Wolf Motor Function Test. We performed a repeated measure study with the recordings taken pre-, post-cTBS, and at 3 months' follow-up.Results: We investigated changes in motor rhythms during arm elevation and thumb opposition tasks and found significant changes in beta power of the affected thumb's opposition, specifically after real cTBS. Our results are consistent with an excitatory response (increase in event-related desynchronization) in the sensorimotor cortical areas of the affected hemisphere, after stimulation. Neither peak-to-peak amplitude of motor-evoked potentials nor motor performance were significantly altered.Conclusions: Consistently with the theoretical prediction, this contralateral inhibitory stimulation paradigm changes neurophysiology, leading to a significant excitatory impact on the cortical oscillatory patterns of the contralateral hemisphere. These proof-of-concept results provide evidence for the potential role of continuous TBS in the neurorehabilitation of post-stroke patients. We suggest that these changes in ERS/ERD patterns should be further explored in future phase IIb/phase III clinical trials, in larger samples of poststroke patients.

Background: Several functional magnetic resonance imaging (fMRI) studies investigated the brain correlates of psychogenic erectile dysfunction (PED) and premature ejaculation (PE), representing the most common sexual dysfunctions in men. These studies allowed a wide set of brain regions in PED and PE patients when compared to healthy men. In the present meta-analysis, we aim at assessing the presence of homogeneity in the cerebral underpinnings of PED and PE. Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and after the electronic search, duplicate removal and the application of pre-exclusion criteria, nine PED and ten PE studies were considered eligible with a Cohen’s k of 0.84 and 0.75, respectively. The effect sizes of the sociodemographic and psychological/urological dimensions were calculated. We extracted brain clusters from the retrieved studies, comparing patients and controls, and we calculated brain maps with Seed-Based D Mapping software. Results: We found a homogenous involvement of the frontal gyrus and insula in both dysfunctions, suggesting a common network. Conclusions: The anterior insula plays a key role in the processing of emotional features of stimuli, while the posterior insula in interoceptive information is relevant for sexual response. The prefrontal and inferior frontal cortices are important for sexual inhibition/disinhibition.

There is an increasing interest in the neural effects of psychoactive drugs, in particular tryptamine psychedelics, which has been incremented by the proposal that they have potential therapeutic benefits, based on their molecular mimicry of serotonin. It is widely believed that they act mainly through 5HT2A receptors but their effects on neural activation of distinct brain systems are not fully understood. We performed a quantitative meta-analysis of brain imaging studies to investigate the effects of substances within this class (e.g., LSD, Psilocybin, DMT, Ayahuasca) in the brain from a molecular and functional point of view. We investigated the question whether the changes in activation patterns and connectivity map into regions with larger 5HT1A/5HT2A receptor binding, as expected from indolaemine hallucinogens (in spite of the often reported emphasis only on 5HT2AR). We did indeed find that regions with changed connectivity and/or activation patterns match regions with high density of 5HT2A receptors, namely visual BA19, visual fusiform regions in BA37, dorsal anterior and posterior cingulate cortex, medial prefrontal cortex, and regions involved in theory of mind such as the surpramarginal gyrus, and temporal cortex (rich in 5HT1A receptors). However, we also found relevant patterns in other brain regions such as dorsolateral prefrontal cortex. Moreover, many of the above-mentioned regions also have a significant density of both 5HT1A/5HT2A receptors, and available PET studies on the effects of psychedelics on receptor occupancy are still quite scarce, precluding a metanalytic approach. Finally, we found a robust neuromodulatory effect in the right amygdala. In sum, the available evidence points towards strong neuromodulatory effects of tryptamine psychedelics in key brain regions involved in mental imagery, theory of mind and affective regulation, pointing to potential therapeutic applications of this class of substances.

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.

Social attention deficits represent a central impairment of patients suffering from autism spectrum disorder (ASD), but the nature of such deficits remains controversial. We compared visual attention regarding social (faces) vs. non-social stimuli (objects), in an ecological diagnostic context, in 46 children and adolescents divided in two groups: ASD (N= 23) and typical neurodevelopment (TD) (N= 23), matched for chronological age and intellectual performance. Eye-tracking measures of visual scanning, while exploring and describing scenes from three different tasks from the Autism Diagnostic Observation Schedule (ADOS), were analyzed: “Description of a Picture,” “Cartoons,” and “Telling a Story from a Book.” Our analyses revealed a three-way interaction between Group, Task, and Social vs. Object Stimuli. We found a striking main effect of group and a task dependence of attentional allocation: while the TD attended first and longer to faces, ASD participants became similar to TD when they were asked to look at pictures while telling a story. Our results suggest that social attention allocation is task dependent, raising the question whether spontaneous attention deficits can be rescued by guiding goal-directed actions.

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.

The ability to perceive and feel another person’ pain as if it were one’s own pain, e.g., pain empathy, is related to brain activity in the “pain-matrix” network. A non-core region of this network in Dorsolateral Prefrontal Cortex (DLPFC) has been suggested as a modulator of the attentional-cognitive dimensions of pain processing in the context of pain empathy. We conducted a neurofeedback experiment using real-time functional magnetic resonance imaging (rt-fMRI-NF) to investigate the association between activity in the left DLPFC (our neurofeedback target area) and the perspective assumed by the participant (“first-person”/“Self” or “third-person”/“Other” perspective of a pain-inducing stimulus), based on a customized pain empathy task. Our main goals were to assess the participants’ ability to volitionally modulate activity in their own DLPFC through an imagery task of pain empathy and to investigate into which extent this ability depends on feedback. Our results demonstrate participants’ ability to significantly modulate brain activity of the neurofeedback target area for the “first-person”/”Self” and “third-person”/”Other” perspectives. Results of both perspectives show that the participants were able to modulate (with statistical significance) the activity already in the first run of the session, in spite of being naïve to the task and even in the absence of feedback information. Moreover, they improved modulation throughout the session, particularly in the “Self” perspective. These results provide new insights on the role of DLPFC in pain and pain empathy mechanisms and validate the proposed protocol, paving the way for future interventional studies in clinical populations with empathic deficits 631E-936F-DCED | Ana Carolina Gonçalves Sousa Travassos N/A

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.