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Recently, there has been a resurgence in experimental and conceptual efforts to understand how brain rhythms can serve to organize visual information. Oscillations can provide temporal structure for neuronal processing and form a basis for integrating information across brain areas. Here, we use a bistable paradigm and a data-driven approach to test the hypothesis that oscillatory modulations associate with the integration or segregation of visual elements. Spectral signatures of perception of bound and unbound configurations of visual moving stimuli were studied using magnetoencephalography (MEG) in ambiguous and unambiguous conditions. Using a 2 × 2 design, we were able to isolate correlates from visual integration, either perceptual or stimulus-driven, from attentional and ambiguity-related activity. Two frequency bands were found to be modulated by visual integration: an alpha/beta frequency and a higher frequency gamma-band. Alpha/beta power was increased in several early visual cortical and dorsal visual areas during visual integration, while gamma-band power was surprisingly increased in the extrastriate visual cortex during segregation. This points to an integrative role for alpha/beta activity, likely from top-down signals maintaining a single visual representation. On the other hand, when more representations have to be processed in parallel gamma-band activity is increased, which is at odds with the notion that gamma oscillations are related to perceptual coherence. These modulations were confirmed in intracranial EEG recordings and partially originate from distinct brain areas. Our MEG and stereo-EEG data confirms predictions of binding mechanisms depending on low-frequency activity for long-range integration and for organizing visual processing while refuting a straightforward correlation between gamma-activity and perceptual binding. PRACTITIONER POINTS: Distinct neurophysiological signals underlie competing bistable percepts. Increased alpha/beta activity correlate with visual integration while gamma correlates with segmentation. Ambiguous percepts drive alpha/beta activity in the posterior cingulate cortex., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Comprehending digital content written in natural language online is vital for many aspects of life, including learning, professional tasks, and decision-making. However, facing comprehension difficulties can have negative consequences for learning outcomes, critical thinking skills, decision-making, error rate, and productivity. This paper introduces an innovative approach to predict comprehension difficulties at the local content level (e.g., paragraphs). Using affordable wearable devices, we acquire physiological responses non-intrusively from the autonomous nervous system, specifically pulse rate variability, and electrodermal activity. Additionally, we integrate data from a cost-effective eye-tracker. Our machine learning algorithms identify 'hotspots' within the content and regions corresponding to a high cognitive load. These hotspots represent real-time predictors of comprehension difficulties. By integrating physiological data with contextual information (such as the levels of experience of individuals), our approach achieves an accuracy of 72.11% ± 2.21, a precision of 0.77, a recall of 0.70, and an f1 score of 0.73. This study opens possibilities for developing intelligent, cognitive-aware interfaces. Such interfaces can provide immediate contextual support, mitigating comprehension challenges within content. Whether through translation, content generation, or content summarization using available Large Language Models, this approach has the potential to enhance language comprehension., (© 2024. The Author(s).)

Cognitive human error and recent cognitive taxonomy on human error causes of software defects support the intuitive idea that, for instance, mental overload, attention slips, and working memory overload are important human causes for software bugs. In this paper, we approach the EEG as a reliable surrogate to MRI-based reference of the programmer's cognitive state to be used in situations where heavy imaging techniques are infeasible. The idea is to use EEG biomarkers to validate other less intrusive physiological measures, that can be easily recorded by wearable devices and useful in the assessment of the developer's cognitive state during software development tasks. Herein, our EEG study, with the support of fMRI, presents an extensive and systematic analysis by inspecting metrics and extracting relevant information about the most robust features, best EEG channels and the best hemodynamic time delay in the context of software development tasks. From the EEG-fMRI similarity analysis performed, we found significant correlations between a subset of EEG features and the Insula region of the brain, which has been reported as a region highly related to high cognitive tasks, such as software development tasks. We concluded that despite a clear inter-subject variability of the best EEG features and hemodynamic time delay used, the most robust and predominant EEG features, across all the subjects, are related to the Hjorth parameter Activity and Total Power features, from the EEG channels F4, FC4 and C4, and considering in most of the cases a hemodynamic time delay of 4 seconds used on the hemodynamic response function. These findings should be taken into account in future EEG-fMRI studies in the context of software debugging., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Medeiros et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Functional neuroimaging can provide pathophysiological information in perinatal asphyxia (PA). However, fundamental unresolved questions remain related to the influence of neurovascular coupling (NVC) maturation on functional responses in early development. We aimed to probe the feasibility and compare the responses to multiple sensory stimulations in newborns with PA using functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS)., Methods: Responses to visual, auditory, and sensorimotor passive stimulation were measured with fMRI and fNIRS and compared in 18 term newborns with PA and six controls., Results: Most newborns exhibited a positive fMRI response during visual and sensorimotor stimulation, higher in the sensorimotor. An asymmetric pattern (negative in the left hemisphere) was observed in auditory stimulation. The fNIRS response most resembling the adult pattern (positive) in PA occurred during auditory stimulation, in which oxyhemoglobin (HbO) increased, and deoxyhemoglobin (HbR) decreased. Significative differences were found in the HbO and HbR profiles in newborns with PA compared to the controls, more evident in auditory stimulation. Positive correlations between the fMRI BOLD signal and at least one fNIRS channel (HbO) in all stimuli in newborns with PA were identified: the strongest was in the auditory (r=0.704) and the weakest in the sensorimotor (r=0.544); in more fNIRS channels, in the visual., Conclusions: Both techniques are feasible physiological assessment tools, suggesting a distinctive level of maturation in sensory and motor areas. Differences in fNIRS profiles in newborns with PA and controls and the fMRI-fNIRS relationship observed can encourage the fNIRS as a clinically emergent valuable tool., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-135/coif). The authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hao, Hijazi, Durães, Medeiros, Couceiro, Lam, Teixeira, Castelhano, Castelo Branco, Carvalho and Madeira.)

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 [ 64 Cu]-ATSM and ex vivo in human skin fibroblasts of premanifest and prodromal (Pre-M) and manifest HD carriers. In vivo brain [ 64 Cu]-ATSM PET in YAC128 transgenic mouse and striatal and cortical isolated mitochondria were assessed at presymptomatic (3 month-old, mo) and symptomatic (6-12 mo) stages. Pre-M HD carriers exhibited enhanced whole-brain (with exception of caudate) [ 64 Cu]-ATSM labelling, correlating with CAG repeat number. Fibroblasts from Pre-M showed enhanced basal and maximal respiration, proton leak and increased hydrogen peroxide (H 2 O 2 ) levels, later progressing in manifest HD. Mitochondria from fibroblasts of Pre-M HD carriers also showed reduced circularity, while higher number of mitochondrial DNA copies correlated with maximal respiratory capacity. In vivo animal PET analysis showed increased accumulation of [ 64 Cu]-ATSM in YAC128 mouse striatum. YAC128 mouse (at 3 months) striatal isolated mitochondria exhibited a rise in basal and maximal mitochondrial respiration and in ATP production, and increased complex II and III activities. YAC128 mouse striatal mitochondria also showed enhanced mitochondrial H 2 O 2 levels and circularity, revealed by brain ultrastructure analysis, and defects in Ca 2+ handling, supporting increased striatal susceptibility. Data demonstrate both human and mouse mitochondrial overactivity and altered morphology at early HD stages, facilitating redox unbalance, the latter progressing with manifest disease., Competing Interests: Declaration of competing interest The authors report no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We 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., Methods: This 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., Results: Real 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)., Conclusion: These 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Abuhaiba, Duarte, Castelhano, Dionísio, Sales, Edden and Castelo-Branco.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Estiveira, Dias, Costa, Castelhano, Castelo-Branco and Sousa.)

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 ( 1 H-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. 1 H-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 1 H-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., (© 2022. The Author(s).)

The neural correlates of software programming skills have been the target of an increasing number of studies in the past few years. Those studies focused on error-monitoring during software code inspection. Others have studied task-related cognitive load as measured by distinct neurophysiological measures. Most studies addressed only syntax errors (shallow level of code monitoring). However, a recent functional MRI (fMRI) study suggested a pivotal role of the insula during error-monitoring when challenging deep-level analysis of code inspection was required. This raised the hypothesis that the insula is causally involved in deep error-monitoring. To confirm this hypothesis, we carried out a new fMRI study where participants performed a deep source-code comprehension task that included error-monitoring to detect bugs in the code. The generality of our paradigm was enhanced by comparison with a variety of tasks related to text reading and bugless source-code understanding. Healthy adult programmers ( N = 21) participated in this 3T fMRI experiment. The activation maps evoked by error-related events confirmed significant activations in the insula [ p (Bonferroni) < 0.05]. Importantly, a posterior-to-anterior causality shift was observed concerning the role of the insula: in the absence of error, causal directions were mainly bottom-up, whereas, in their presence, the strong causal top-down effects from frontal regions, in particular, the anterior cingulate cortex was observed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Castelhano, Duarte, Couceiro, Medeiros, Duraes, Afonso, Madeira and Castelo-Branco.)

Invasive brain recordings using many electrodes across a wide range of tasks provide a unique opportunity to study the role of oscillatory patterning and functional connectivity. We used large-scale recordings (stereo EEG) within and beyond the human hippocampus to investigate the role of distinct frequency oscillations during real-time execution of visual, attention and memory tasks in eight epileptic patients. We found that activity patterns in the hippocampus showed task and frequency dependent properties. Importantly, we found distinct connectivity signatures, in particular concerning parietal-hippocampal connectivity, thus revealing large scale synchronization of networks involved in memory tasks. Comparing the power per frequency band, across tasks and hippocampal regions (anterior/posterior) we confirmed a main effect of frequency band (p = 0.002). Gamma band activity was higher for visuo-spatial memory tasks in the anterior hippocampus. Further, we found that alpha and beta band activity in posterior hippocampus had larger modulation for high memory load visual tasks (p = 0.004). Three functional connectivity task related networks were identified: (dorsal) parietal-hippocampus (visual attention and memory), ventral stream- hippocampus and hippocampal-frontal connections (mainly tasks involving face recognition or object based search). These findings support the critical role of oscillatory patterning in the hippocampus during visual and memory tasks and suggests the presence of task related spectral and functional connectivity signatures. These results show that the use of large scale human intracranial recordings can validate the role of oscillatory and functional connectivity patterns across a broad range of cognitive domains., (© 2022. The Author(s).)

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., Competing Interests: The authors declare there are no competing interests., (©2022 Dias et al.)

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., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Ana Dionísio et al.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dionísio, Gouveia, Castelhano, Duarte, Santo, Sargento-Freitas, Duecker and Castelo-Branco.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Castelhano, Lima, Teixeira, Soares, Pais and Castelo-Branco.)

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., Competing Interests: The authors have no conflicts of interest., (Copyright © 2021 Joao Castelhano et al.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mouga, Castelhano, Café, Sousa, Duque, Oliveira and Castelo-Branco.)

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.

Blood-brain barrier (BBB) disruption is a common feature in neurodegenerative diseases. However, BBB integrity has not been assessed in spinocerebellar ataxias (SCAs) such as Machado-Joseph disease/SCA type 3 (MJD/SCA3), a genetic disorder, triggered by polyglutamine-expanded ataxin-3. To investigate that, BBB integrity was evaluated in a transgenic mouse model of MJD and in human post-mortem brain tissues.Firstly, we investigated the BBB permeability in MJD mice by: i) assessing the extravasation of the Evans blue (EB) dye and blood-borne proteins (e.g fibrinogen) in the cerebellum by immunofluorescence, and ii) in vivo Dynamic Contrast Enhanced-Magnetic Resonance Imaging (DCE-MRI). The presence of ataxin-3 aggregates in brain blood vessels and the levels of tight junction (TJ)-associated proteins were also explored by immunofluorescence and western blotting. Human brain samples were used to confirm BBB permeability by evaluating fibrinogen extravasation, co-localization of ataxin-3 aggregates with brain blood vessels and neuroinflammation.In the cerebellum of the mouse model of MJD, there was a 5-fold increase in EB accumulation when compared to age-matched controls. Moreover, vascular permeability displayed a 13-fold increase demonstrated by DCE-MRI. These results were validated by the 2-fold increase in fibrinogen extravasation in transgenic animals comparing to controls. Interestingly, mutant ataxin-3 aggregates were detected in cerebellar blood vessels of transgenic mice, accompanied by alterations of TJ-associated proteins in cerebellar endothelial cells, namely a 29% decrease in claudin-5 oligomers and a 10-fold increase in an occludin cleavage fragment. These results were validated in post-mortem brain samples from MJD patients as we detected fibrinogen extravasation across BBB, the presence of ataxin-3 aggregates in blood vessels and associated microgliosis.Altogether, our results prove BBB impairment in MJD/SCA3. These findings contribute for a better understanding of the disease mechanisms and opens the opportunity to treat MJD with medicinal products that in normal conditions would not cross the BBB.

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., (Copyright © 2020 Travassos, Sayal, Direito, Castelhano and Castelo-Branco.)

Background: It 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., Methods: We 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., Results: The 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., Conclusions: Our 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.

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., (© The Author(s) 2019. Published by Oxford University Press.)

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., (Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Positron emission tomography (PET) neuroimaging with the Pittsburgh Compound&#95;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 Aβ 38 , Aβ 40 and Aβ 42 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. Aβ 38 and Aβ 40 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 Aβ 42 , the Aβ 42 /Aβ 40 or Aβ 42 /Aβ 38 ratios were found compared to normalization based on cerebellar gray matter.

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 (<45Hz) dominating in the anterior semantic ventral object processing and dorsoventral integrating networks and evolving later, during perceptual decision phases, than early sensory posterior patterns (60-250Hz). This suggests that accurate object recognition/perceptual decision-making is related to distinct spatiotemporal signatures in the low gamma frequency range.

Microvascular dysfunction has been suggested to trigger adipose tissue dysfunction in obesity. This study investigates the hypothesis that glycation impairs microvascular architecture and expandability with an impact on insulin signalling. Animal models supplemented with methylglyoxal (MG), maintained with a high-fat diet (HFD) or both (HFDMG) were studied for periepididymal adipose (pEAT) tissue hypoxia and local and systemic insulin resistance. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantify blood flow in vivo, showing MG-induced reduction of pEAT blood flow. Increased adipocyte size and leptin secretion were observed only in rats feeding the high-fat diet, without the development of hypoxia. In turn, hypoxia was only observed when MG was combined (HFDMG group), being associated with impaired activation of the insulin receptor (Tyr1163), glucose intolerance and systemic and muscle insulin resistance. Accordingly, the adipose tissue angiogenic assay has shown decreased capillarization after dose-dependent MG exposure and glyoxalase-1 inhibition. Thus, glycation impairs adipose tissue capillarization and blood flow, hampering its expandability during a high-fat diet challenge and leading to hypoxia and insulin resistance. Such events have systemic repercussions in glucose metabolism and may lead to the onset of unhealthy obesity and progression to type 2 diabetes.

Introduction: Hippocampal oscillations have been regularly described as playing a dominant role in spatial memory and navigation in rodents. In humans, the relative role of anterior versus posterior rhythms during navigational memory is not established., Methods: Here, we tested this hypothesis using direct brain ECoG recordings in the anterior and posterior hippocampus of a patient, in a navigational task requiring spatial memory. We assessed multiple oscillatory bands during encoding and retrieval phases., Results: We found navigation related 1-3.5 Hz activity during retrieval, both in the anterior and posterior hippocampus. Activity between 4 and 8 Hz was identified during both encoding and retrieval, only in the anterior hippocampus., Conclusions: Our findings are consistent with the view that an anterior/posterior functional gradient is present in the hippocampus, and involves two distinct neuronal networks, supporting either encoding or retrieval processes . Although this is a single case scenario, these findings suggest that neural oscillations during spatial navigation do vary across hippocampal subregions, as a function of encoding versus retrieval processes during the mnemonic process. In this single case study, the results point to the presence of a dual involvement of multiple frequency bands across hippocampal subregions during encoding and retrieval. Although these results need generalization, they provide a new perspective on distinct physiological properties of the anterior and posterior hippocampus in human spatial navigation during encoding and retrieval.

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.

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., (Copyright © 2014 Wiley Periodicals, Inc.)

The relation of gamma-band synchrony to holistic perception in which concerns the effects of sensory processing, high level perceptual gestalt formation, motor planning and response is still controversial. To provide a more direct link to emergent perceptual states we have used holistic EEG/ERP paradigms where the moment of perceptual "discovery" of a global pattern was variable. Using a rapid visual presentation of short-lived Mooney objects we found an increase of gamma-band activity locked to perceptual events. Additional experiments using dynamic Mooney stimuli showed that gamma activity increases well before the report of an emergent holistic percept. To confirm these findings in a data driven manner we have further used a support vector machine classification approach to distinguish between perceptual vs. non perceptual states, based on time-frequency features. Sensitivity, specificity and accuracy were all above 95%. Modulations in the 30-75 Hz range were larger for perception states. Interestingly, phase synchrony was larger for perception states for high frequency bands. By focusing on global gestalt mechanisms instead of local processing we conclude that gamma-band activity and synchrony provide a signature of holistic perceptual states of variable onset, which are separable from sensory and motor processing.