Functional reorganization of memory processing in the hippocampus is associated with neuroprotector GLP-1 levels in type 2 diabetes.

Type 2 diabetes (T2D) often impairs memory functions, suggesting specific vulnerability of the hippocampus. In vivo neuroimaging studies relating encoding and retrieval of memory information with endogenous neuroprotection are lacking. The neuroprotector glucagon-like peptide (GLP-1) has a high receptor density in anterior/ventral hippocampus, as shown by animal models. Using an innovative event-related fMRI design in 34 participants we investigated patterns of hippocampal activity in T2D (n = 17) without mild cognitive impairment (MCI) versus healthy controls (n = 17) during an episodic memory task. We directly measured neurovascular coupling by estimating the hemodynamic response function using event-related analysis related to encoding and retrieval of episodic information in the hippocampus. We applied a mixed-effects general linear model analysis and a two-factor ANOVA to test for group differences. Significant between-group differences were found for memory encoding, showing evidence for functional reorganization: T2D patients showed an augmented activation in the posterior hippocampus while anterior activation was reduced. The latter was negatively correlated with both GLP-1 pre- and post-breakfast levels, in the absence of grey matter changes. These results suggest that patients with T2D without MCI have pre-symptomatic functional reorganization in brain regions underlying episodic memory, as a function of the concentration of the neuroprotective neuropeptide GLP-1.

Trust-based health decision-making recruits the neural interoceptive saliency network which relates to temporal trajectories of Hemoglobin A1C in Diabetes Type 1.

Experimental approaches in neuroeconomics generally involve monetary utility. Utility in the health domain is relevant in diabetes because constant daily life decisions are critical for self-consequential long-term outcomes. We used fMRI to investigate self-consequent decision-making in the health and economic domains in Type 1 Diabetes Mellitus and controls (N = 50). We focused on two critical phases of decision-making: Investment and Feedback (Positive or Negative). Patients showed larger BOLD activation of limbic, and reward/dopaminergic regions in particular in the health trust game. Importantly, the worse the trajectory of metabolic control (increasing HbA1C), the higher the BOLD activity in regions of the interoceptive saliency network. This was manifested by positive correlations between brain activity during investment in anterior cingulate cortex and insula and HbA1c blood level progression. We conclude that the neural correlates of health-consequent decision-making domain involve limbic and reward related dopaminergic regions in Type 1 Diabetes Mellitus. Furthermore, the temporal trajectory of HbA1C blood levels is correlated with neural risk processing in the saliency network. Evidence for differential risk processing in the health versus the neuroeconomic context, and the discovery of a role for the saliency interoceptive network in metabolic control trajectories suggests a new perspective on the development of personalized interventions.

Functional neuroimaging of responses to multiple sensory stimulations in newborns with perinatal asphyxia.

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.

Neural correlates of fanhood: the role of fan identity and team brand strength.

Introduction: We analyzed the importance of fan identity and brand strength on fans' neural reactions to different team-related stimuli. Methods: A total of 53 fMRI scans with fans of two professional sport teams were conducted. Following up on a previous study we focused on the differences between fandom levels as well as the contrast between two team "brand" strength. Neural responses were compared among individuals based on their levels of fan identity. In sum, group comparisons between relatively high and lower identity and between weak and strong teams were made based on the notion that the latter reflects team brand strength (strong brand and weak brand). Results: Findings indicate that brain activity in emotion regulation, memory, and cognitive control circuits is influenced by the relative level of fan identity. Discussion: Higher-level identified fans showed increased reactivity to positive stimuli and the under-recruitment of their cognitive appraisal circuits, suggesting more vulnerability to marketers' messages. The strength of the team brand activates different neural mechanisms. Interestingly, the posterior cingulate showed larger recruitment both for weaker brands and lower fan identification, suggesting that visual memory processes are more active in these cases. Neurally processed content depends on the relative brand's strength, highlighting the importance of brand-focused communications.

Trust-Based Decision-Making in the Health Context Discriminates Biological Risk Profiles in Type 1 Diabetes.

Theoretical accounts on social decision-making under uncertainty postulate that individual risk preferences are context dependent. Generalization of models of decision-making to dyadic interactions in the personal health context remain to be experimentally addressed. In economic utility-based models, interactive behavioral games provide a framework to investigate probabilistic learning of sequential reinforcement. Here, we model an economic trust game in the context of a chronic disease (Diabetes Type 1) which involves iterated daily decisions in complex social contexts. Ninety-one patients performed experimental trust games in both economic and health settings and were characterized by a multiple self-report set of questionnaires. We found that although our groups can correctly infer pay-off contingencies, they behave differently because patients with a biological profile of preserved glycemic control show adaptive choice behavior both in economic and health domains. On the other hand, patients with a biological profile of loss of glycemic control presented a contrasting behavior, showing non-adaptive choices on both contexts. These results provide a direct translation from neuroeconomics to decision-making in the health domain and biological risk profiles, in a behavioral setting that requires difficult and self-consequential decisions with health impact. Our findings also provide a contextual generalization of mechanisms underlying individual decision-making under uncertainty.

The impact of cathodal tDCS on the GABAergic system in the epileptogenic zone: A multimodal imaging study.

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.

Software Bug Detection Causes a Shift From Bottom-Up to Top-Down Effective Connectivity Involving the Insula Within the Error-Monitoring Network.

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.

Abnormal Responses in Cognitive Impulsivity Circuits Are Associated with Glycosylated Hemoglobin Trajectories in Type 1 Diabetes Mellitus and Impaired Metabolic Control.

BACKGROUND: Risky health decisions and impulse control profiles may impact on metabolic control in type 1 diabetes mellitus (T1DM). We hypothesize that the neural correlates of cognitive impulsivity and decision-making in T1DM relate to metabolic control trajectories. METHODS: We combined functional magnetic resonance imaging (fMRI), measures of metabolic trajectories (glycosylated hemoglobin [HbA1c] over multiple time points) and behavioral assessment using a cognitive impulsivity paradigm, the Balloon Analogue Risk Task (BART), in 50 participants (25 T1DM and 25 controls). RESULTS: Behavioral results showed that T1DM participants followed a rigid conservative risk strategy along the iterative game. Imaging group comparisons showed that patients showed larger activation of reward related, limbic regions (nucleus accumbens, amygdala) and insula (interoceptive saliency network) in initial game stages. Upon game completion differences emerged in relation to error monitoring (anterior cingulate cortex [ACC]) and inhibitory control (inferior frontal gyrus). Importantly, activity in the saliency network (ACC and insula), which monitors interoceptive states, was related with metabolic trajectories, which was also found for limbic/reward networks. Parietal and posterior cingulate regions activated both in controls and patients with adaptive decision-making, and positively associated with metabolic trajectories. CONCLUSION: We found triple converging evidence when comparing metabolic trajectories, patients versus controls or risk averse (non-learners) versus patients who learned by trial and error. Dopaminergic reward and saliency (interoceptive and error monitoring) circuits show a tight link with impaired metabolic trajectories and cognitive impulsivity in T1DM. Activity in parietal and posterior cingulate are associated with adaptive trajectories. This link between reward-saliency-inhibition circuits suggests novel strategies for patient management.

Reading and Calculation Neural Systems and Their Weighted Adaptive Use for Programming Skills.

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.

Successful metabolic control in diabetes type 1 depends on individual neuroeconomic and health risk-taking decision endophenotypes: a new target in personalized care.

BACKGROUND: Neurobehavioral decision profiles have often been neglected in chronic diseases despite their direct impact on major public health issues such as treatment adherence. This remains a major concern in diabetes, despite intensive efforts and public awareness initiatives regarding its complications. We hypothesized that high rates of low adherence are related to risk-taking profiles associated with decision-making phenotypes. If this hypothesis is correct, it should be possible to define these endophenotypes independently based both on dynamic measures of metabolic control (HbA1C) and multidimensional behavioral profiles. METHODS: In this study, 91 participants with early-stage type 1 diabetes fulfilled a battery of self-reported real-world risk behaviors and they performed an experimental task, the Balloon Analogue Risk Task (BART). RESULTS: K-means and two-step cluster analysis suggest a two-cluster solution providing information of distinct decision profiles (concerning multiple domains of risk-taking behavior) which almost perfectly match the biological partition, based on the division between stable or improving metabolic control (MC, N = 49) v. unstably high or deteriorating states (NoMC, N = 42). This surprising dichotomy of behavioral phenotypes predicted by the dynamics of HbA1C was further corroborated by standard statistical testing. Finally, the BART game enabled to identify groups differences in feedback learning and consequent behavioral choices under ambiguity, showing distinct group choice behavioral patterns. CONCLUSIONS: These findings suggest that distinct biobehavioral endophenotypes can be related to the success of metabolic control. These findings also have strong implications for programs to improve patient adherence, directly addressing risk-taking profiles.

The role of the insula in intuitive expert bug detection in computer code: an fMRI study.

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.

Cortical functional topography of high-frequency gamma activity relates to perceptual decision: an Intracranial study.

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.

Tribal love: the neural correlates of passionate engagement in football fans.

The tribal character of the affective link between football fans and their teams is a well-recognized phenomenon. Other forms of love such as romantic or maternal attachment have previously been studied from a neuroimaging point of view. Here we aimed to investigate the neural basis of this tribal form of love, which implies both the feeling of belongingness and rivalry against opposing teams. A pool of 56 participants was submitted to an fMRI experimental design involving the presentation of winning and losing football moments of their loved, rival or neutral teams. We found recruitment of amygdala and reward regions, including the ventral tegmental area (VTA) and substantia nigra (SN), as well as other limbic regions involved in emotional cognition, for 'positive vs neutral' and 'positive vs negative' conditions. The latter contrast was correlated with neuropsychological scores of fanaticism in the amygdala and regions within the reward system, as the VTA and SN. The observation of increased response patterns in critical components of the reward system, in particular for positive content related to the loved team, suggests that this kind of non-romantic love reflects a specific arousal and motivational state, which is biased for emotional learning of positive outcomes.

The anterior versus posterior hippocampal oscillations debate in human spatial navigation: evidence from an electrocorticographic case study.

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.

Discovery of novel plant peptides as strong inhibitors of metalloproteinases.

Five novel metalloproteinase protein inhibitors (MPIs) with molecular mass between 5.6 and 8.9 kDa and acid/neutral pI were detected in lupin seeds and exhibited strong inhibitory activities against thermolysin and/or gelatinase B. These novel peptides constitute not only the first MPIs described in plants but also the first plant peptides with inhibitory activity against a matrixin.