The effect of a cognitive training therapy based on stimulation of brain oscillations in patients with mild cognitive impairment in a Chilean sample: study protocol for a phase IIb, 2 × 3 mixed factorial, double-blind randomised controlled trial.

BACKGROUND: The ageing population has increased the prevalence of disabling and high-cost diseases, such as dementia and mild cognitive impairment (MCI). The latter can be considered a prodromal phase of some dementias and a critical stage for interventions to postpone the impairment of functionality. Working memory (WM) is a pivotal cognitive function, representing the fundamental element of executive functions. This project proposes an intervention protocol to enhance WM in these users, combining cognitive training with transcranial electrical stimulation of alternating current (tACS). This technique has been suggested to enhance the neuronal plasticity needed for cognitive processes involving oscillatory patterns. WM stands to benefit significantly from this approach, given its well-defined electrophysiological oscillations. Therefore, tACS could potentially boost WM in patients with neurodegenerative diseases. METHODS: This study is a phase IIb randomised, double-blind clinical trial with a 3-month follow-up period. The study participants will be 62 participants diagnosed with MCI, aged over 60, from Valparaíso, Chile. Participants will receive an intervention combining twelve cognitive training sessions with tACS. Participants will receive either tACS or placebo stimulation in eight out of twelve training sessions. Sessions will occur twice weekly over 6 weeks. The primary outcomes will be electroencephalographic measurements through the prefrontal theta oscillatory activity, while the secondary effects will be cognitive assessments of WM. The participants will be evaluated before, immediately after, and 3 months after the end of the intervention. DISCUSSION: The outcomes of this trial will add empirical evidence about the benefits and feasibility of an intervention that combines cognitive training with non-invasive brain stimulation. The objective is to contribute tools for optimal cognitive treatment in patients with MCI. To enhance WM capacity, postpone the impairment of functionality, and obtain a better quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05291208. Registered on 28 February 2022. ISRCTN87597719 retrospectively registered on 15 September 2023.

Dominance hierarchy regulates social behavior during spatial movement.

Rodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known about its significance in other social behaviors, for instance during collective navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial task in mice, in which animals navigated individually or collectively with their littermates foraging for food. We compared between conditions and found that the social condition exerts significant influence on individual displacement patterns, even when efficient navigation rules leading to reward had been previously learned. Thus, movement patterns and consequent task performance were strongly dependent on contingent social interactions arising during collective displacement, yet their influence on individual behavior was determined by dominance hierarchy. Dominant animals did not behave as leaders during collective displacement; conversely, they were most sensitive to the social environment adjusting their performance accordingly. Social ranking in turn was associated with specific spontaneous neural activity patterns in the prefrontal cortex and hippocampus, with dominant mice showing higher firing rates, larger ripple oscillations, and stronger neuronal entrainment by ripples than subordinate animals. Moreover, dominant animals selectively increased their cortical spiking activity during collective movement, while subordinate mice did not modify their firing rates, consistent with dominant animals being more sensitive to the social context. These results suggest that dominance hierarchy influences behavioral performance during contingent social interactions, likely supported by the coordinated activity in the hippocampal-prefrontal circuit.

Oscillatory activity underlying cognitive performance in children and adolescents with autism: a systematic review.

Autism spectrum disorder (ASD) is a neurodevelopmental condition that exhibits a widely heterogeneous range of social and cognitive symptoms. This feature has challenged a broad comprehension of this neurodevelopmental disorder and therapeutic efforts to address its difficulties. Current therapeutic strategies have focused primarily on treating behavioral symptoms rather than on brain psychophysiology. During the past years, the emergence of non-invasive brain stimulation techniques (NIBS) has opened alternatives to the design of potential combined treatments focused on the neurophysiopathology of neuropsychiatric disorders like ASD. Such interventions require identifying the key brain mechanisms underlying the symptomatology and cognitive features. Evidence has shown alterations in oscillatory features of the neural ensembles associated with cognitive functions in ASD. In this line, we elaborated a systematic revision of the evidence of alterations in brain oscillations that underlie key cognitive processes that have been shown to be affected in ASD during childhood and adolescence, namely, social cognition, attention, working memory, inhibitory control, and cognitive flexibility. This knowledge could contribute to developing therapies based on NIBS to improve these processes in populations with ASD.

The parietal cortex has a causal role in ambiguity computations in humans.

Humans often face the challenge of making decisions between ambiguous options. The level of ambiguity in decision-making has been linked to activity in the parietal cortex, but its exact computational role remains elusive. To test the hypothesis that the parietal cortex plays a causal role in computing ambiguous probabilities, we conducted consecutive fMRI and TMS-EEG studies. We found that participants assigned unknown probabilities to objective probabilities, elevating the uncertainty of their decisions. Parietal cortex activity correlated with the objective degree of ambiguity and with a process that underestimates the uncertainty during decision-making. Conversely, the midcingulate cortex (MCC) encodes prediction errors and increases its connectivity with the parietal cortex during outcome processing. Disruption of the parietal activity increased the uncertainty evaluation of the options, decreasing cingulate cortex oscillations during outcome evaluation and lateral frontal oscillations related to value ambiguous probability. These results provide evidence for a causal role of the parietal cortex in computing uncertainty during ambiguous decisions made by humans.

Another in need enhances prosociality and modulates frontal theta oscillations in young adults.

Introduction: Decision-making is a process that can be strongly affected by social factors. Evidence has shown how people deviate from traditional rational-choice predictions under different levels of social interactions. The emergence of prosocial decision-making, defined as any action that is addressed to benefit another individual even at the expense of personal benefits, has been reported as an example of such social influence. Furthermore, brain evidence has shown the involvement of structures such as the prefrontal cortex, anterior insula, and midcingulate cortex during decision settings in which a decision maker interacts with others under physical pain or distress or while being observed by others. Methods: Using a slightly modified version of the dictator game and EEG recordings, we tested the hypothesis that the inclusion of another person into the decision setting increases prosocial decisions in young adults and that this increase is higher when the other person is associated with others in need. At the brain level, we hypothesized that the increase in prosocial decisions correlates with frontal theta activity. Results and Discussion: The results showed that including another person in the decision, setting increased prosocial behavior only when this presence was associated with someone in need. This effect was associated with an increase in frontocentral theta-oscillatory activity. These results suggest that the presence of someone in need enhances empathy concerns and norm compliance, raising the participants' prosocial decision-making.

Country-level gender inequality is associated with structural differences in the brains of women and men.

Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.

Functional Dizziness as a Spatial Cognitive Dysfunction.

(1) Background: Persistent postural-perceptual dizziness (PPPD) is a common chronic dizziness disorder with an unclear pathophysiology. It is hypothesized that PPPD may involve disrupted spatial cognition processes as a core feature. (2) Methods: A cohort of 19 PPPD patients underwent psycho-cognitive testing, including assessments for anxiety, depression, memory, attention, planning, and executive functions, with an emphasis on spatial navigation via a virtual Morris water maze. These patients were compared with 12 healthy controls and 20 individuals with other vestibular disorders but without PPPD. Vestibular function was evaluated using video head impulse testing and vestibular evoked myogenic potentials, while brain magnetic resonance imaging was used to exclude confounding pathology. (3) Results: PPPD patients demonstrated unique impairments in allocentric spatial navigation (as evidenced by the virtual Morris water maze) and in other high-demand visuospatial cognitive tasks that involve executive functions and planning, such as the Towers of London and Trail Making B tests. A factor analysis highlighted spatial navigation and advanced visuospatial functions as being central to PPPD, with a strong correlation to symptom severity. (4) Conclusions: PPPD may broadly impair higher cognitive functions, especially in spatial cognition. We discuss a disruption in the creation of enriched cognitive spatial maps as a possible pathophysiology for PPPD.

Brain structural parameters correlate with University Selection Test outcomes in Chilean high school graduates.

How well students learn and perform in academic contexts is a focus of interest for the students, their families, and the entire educational system. Although evidence has shown that several neurobiological factors are involved in scholastic achievement (SA), specific brain measures associated with academic outcomes and whether such associations are independent of other factors remain unclear. This study attempts to identify the relationship between brain structural parameters, and the Chilean national University Selection Test (PSU) results in high school graduates within a multidimensional approach that considers socio-economic, intellectual, nutritional, and demographic variables. To this end, the brain morphology of a sample of 102 students who took the PSU test was estimated using Magnetic Resonance Imaging. Anthropometric parameters, intellectual ability (IA), and socioeconomic status (SES) were also measured. The results revealed that, independently of sex, IA, gray matter volume, right inferior frontal gyrus thickness, and SES were significantly associated with SA. These findings highlight the role of nutrition, health, and socioeconomic variables in academic success.

Differences in cortical processing of facial emotions in broader autism phenotype.

Autism Spectrum Disorder (ASD) is a heterogeneous condition that affects face perception. Evidence shows that there are differences in face perception associated with the processing of low spatial frequency (LSF) and high spatial frequency (HSF) of visual stimuli between non-symptomatic relatives of individuals with autism (broader autism phenotype, BAP) and typically developing individuals. However, the neural mechanisms involved in these differences are not fully understood. Here we tested whether face-sensitive event related potentials could serve as neuronal markers of differential spatial frequency processing, and whether these potentials could differentiate non-symptomatic parents of children with autism (pASD) from parents of typically developing children (pTD). To this end, we performed electroencephalographic recordings of both groups of parents while they had to recognize emotions of face pictures composed of the same or different emotions (happiness or anger) presented in different spatial frequencies. We found no significant differences in the accuracy between groups but lower amplitude modulation in the Late Positive Potential activity in pASD. Source analysis showed a difference in the right posterior part of the superior temporal region that correlated with ASD symptomatology of the child. These results reveal differences in brain processing of recognition of facial emotion in BAP that could be a precursor of ASD.

Explicit and implicit markers of fairness preeminence in criminal judges.

Achieving justice could be considered a complex social decision-making scenario. Despite the relevance of social decisions for legal contexts, these processes have still not been explored for individuals who work as criminal judges dispensing justice. To bridge the gap, we used a complex social decision-making task (Ultimatum game) and tracked a heart rate variability measurement: the square root of the mean squared differences of successive NN intervals (RMSSD) at their baseline (as an implicit measurement that tracks emotion regulation behavior) for criminal judges (n = 24) and a control group (n = 27). Our results revealed that, compared to controls, judges were slower and rejected a bigger proportion of unfair offers. Moreover, the rate of rejections and the reaction times were predicted by higher RMSSD scores for the judges. This study provides evidence about the impact of legal background and expertise in complex social decision-making. Our results contribute to understanding how expertise can shape criminal judges' social behaviors and pave the way for promising new research into the cognitive and physiological factors associated with social decision-making.

Anatomical dissociation of intracerebral signals for reward and punishment prediction errors in humans.

Whether maximizing rewards and minimizing punishments rely on distinct brain systems remains debated, given inconsistent results coming from human neuroimaging and animal electrophysiology studies. Bridging the gap across techniques, we recorded intracerebral activity from twenty participants while they performed an instrumental learning task. We found that both reward and punishment prediction errors (PE), estimated from computational modeling of choice behavior, correlate positively with broadband gamma activity (BGA) in several brain regions. In all cases, BGA scaled positively with the outcome (reward or punishment versus nothing) and negatively with the expectation (predictability of reward or punishment). However, reward PE were better signaled in some regions (such as the ventromedial prefrontal and lateral orbitofrontal cortex), and punishment PE in other regions (such as the anterior insula and dorsolateral prefrontal cortex). These regions might therefore belong to brain systems that differentially contribute to the repetition of rewarded choices and the avoidance of punished choices.

Late Frontal Negativity Discriminates Outcomes and Intentions in Trust-Repayment Behavior.

Altruism (a costly action that benefits others) and reciprocity (the repayment of acts in kind) differ in that the former expresses preferences about the outcome of a social interaction, whereas the latter requires, in addition, ascribing intentions to others. Interestingly, an individual's behavior and neurophysiological activity under outcome- versus intention-based interactions has not been compared directly using different endowments in the same subject and during the same session. Here, we used a mixed version of the Dictator and the Investment games, together with electroencephalography, to uncover a subject's behavior and brain activity when challenged with endowments of different sizes in contexts that call for an altruistic (outcome-based) versus a reciprocal (intention-based) response. We found that subjects displayed positive or negative reciprocity (reciprocal responses greater or smaller than that for altruism, respectively) depending on the amount of trust they received. Furthermore, a subject's late frontal negativity differed between conditions, predicting responses to trust in intentions-based trials. Finally, brain regions related with mentalizing and cognitive control were the cortical sources of this activity. Thus, our work disentangles the behavioral components present in the repayment of trust, and sheds light on the neural activity underlying the integration of outcomes and perceived intentions in human economic interactions.

Neural Dynamics of Improved Bimodal Attention and Working Memory in Musically Trained Children.

Attention and working memory (WM) are core components of executive functions, and they can be enhanced by training. One activity that has shown to improve executive functions is musical training, but the brain networks underlying these improvements are not well known. We aimed to identify, using functional MRI (fMRI), these networks in children who regularly learn and play a musical instrument. Girls and boys aged 10-13 with and without musical training completed an attention and WM task while their brain activity was measured with fMRI. Participants were presented with a pair of bimodal stimuli (auditory and visual) and were asked to pay attention only to the auditory, only to the visual, or to both at the same time. The stimuli were afterward tested with a memory task in order to confirm attention allocation. Both groups had higher accuracy on items that they were instructed to attend, but musicians had an overall better performance on both memory tasks across attention conditions. In line with this, musicians showed higher activation than controls in cognitive control regions such as the fronto-parietal control network during all encoding phases. In addition, facilitated encoding of auditory stimuli in musicians was positively correlated with years of training and higher activity in the left inferior frontal gyrus and the left supramarginal gyrus, structures that support the phonological loop. Taken together, our results elucidate the neural dynamics that underlie improved bimodal attention and WM of musically trained children and contribute new knowledge to this model of brain plasticity.

Lateral Prefrontal Theta Oscillations Reflect Proactive Cognitive Control Impairment in Males With Attention Deficit Hyperactivity Disorder.

Attention Deficit Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder in which children present prefrontal cortex (PFC) related functions deficit. Proactive cognitive control is a process that anticipates the requirement of cognitive control and crucially depends on the maturity of the PFC. Since this process is important to ADHD symptomatology, we here test the hypothesis that children with ADHD have proactive cognitive control impairments and that these impairments are reflected in the PFC oscillatory activity. We recorded EEG signals from 29 male children with ADHD and 25 typically developing (TD) male children while they performed a Go-Nogo task, where the likelihood of a Nogo stimulus increased while a sequence of consecutive Go stimuli elapsed. TD children showed proactive cognitive control by increasing their reaction time (RT) concerning the number of preceding Go stimuli, whereas children with ADHD did not. This adaptation was related to modulations in both P3a potential and lateral prefrontal theta oscillation for TD children. Children with ADHD as a group did not demonstrate either P3a or theta modulation. But, individual variation in theta activity was correlated with the ADHD symptomatology. The results depict a neurobiological mechanism of proactive cognitive control impairments in children with ADHD.

Frontoparietal connectivity correlates with working memory performance in multiple sclerosis.

Working Memory (WM) impairment is the most common cognitive deficit of patients with Multiple Sclerosis (MS). However, evidence of its neurobiological mechanisms is scarce. Here we recorded electroencephalographic activity of twenty patients with relapsing-remitting MS and minimal cognitive deficit, and 20 healthy control (HC) subjects while they solved a WM task. In spite of similar performance, the HC group demonstrated both a correlation between temporoparietal theta activity and memory load, and a correlation between medial frontal theta activity and successful memory performances. MS patients did not show theses correlations leading significant differences between groups. Moreover, cortical connectivity analyses using granger causality and phase-amplitude coupling between theta and gamma revealed that HC group, but not MS group, presented a load-modulated progression of the frontal-to-parietal connectivity. This connectivity correlated with working memory capacity in MS groups. This early alterations in the oscillatory dynamics underlaying working memory could be useful for plan therapeutic interventions.

Human Anterior Insula Encodes Performance Feedback and Relays Prediction Error to the Medial Prefrontal Cortex.

Adaptive behavior requires the comparison of outcome predictions with actual outcomes (e.g., performance feedback). This process of performance monitoring is computed by a distributed brain network comprising the medial prefrontal cortex (mPFC) and the anterior insular cortex (AIC). Despite being consistently co-activated during different tasks, the precise neuronal computations of each region and their interactions remain elusive. In order to assess the neural mechanism by which the AIC processes performance feedback, we recorded AIC electrophysiological activity in humans. We found that the AIC beta oscillations amplitude is modulated by the probability of performance feedback valence (positive or negative) given the context (task and condition difficulty). Furthermore, the valence of feedback was encoded by delta waves phase-modulating the power of beta oscillations. Finally, connectivity and causal analysis showed that beta oscillations relay feedback information signals to the mPFC. These results reveal that structured oscillatory activity in the anterior insula encodes performance feedback information, thus coordinating brain circuits related to reward-based learning.

A multifactorial approach of nutritional, intellectual, brain development, cardiovascular risk, socio-economic, demographic and educational variables affecting the scholastic achievement in Chilean students: An eight- year follow-up study.

The aim of this study was to quantitate the relative impact of nutritional, intellectual, brain development, cardiovascular risk, socio-economic, demographic and educational variables on the results of the 2009 Quality Education Measurement System (SIMCE) tests of language and mathematics for scholastic achievement (SA) applying a multifactorial approach, in school-age children of the 2010 5th elementary school grade (5ESG) and of the 1st grade of high school (1HSG). The purposes were: i) to test the hypothesis that intellectual ability, the level of SA of the educational establishments in the 2009 SIMCE tests, sex, parental schooling levels, and head circumference-for-age Z-score are the most relevant parameters associated with 2009 SIMCE outcomes; ii) to determine the predictive ability of the 2009 SIMCE results in determining the 2013 SIMCE outcomes for the 2010 5ESG cohort (when they graduated from elementary school, 8th grade) and for determining the 2013 University Selection Test (PSU) outcomes for the 2010 1HSG group (for university admission, when they graduated from high school, 4th grade); iii) to determine the association between the 2009 SIMCE results with the 2017 PSU outcomes for the 2010 5ESG group (for university admission, when they graduated from high school, 4th grade). A representative, proportional and stratified sample of 33 schools of the Metropolitan Region of Chile was randomly chosen. In these schools, 1,353 school-age children of both sexes, of the 2010 5ESG (n = 682; mean age = 10.8 years, SD = 0.6) and of the 2010 1HSG (n = 671; mean age = 14.8 years, SD = 0.6) participated. In both grades and tests, the findings confirm the hypotheses formulated. 2009 SIMCE outcomes were positively and significantly associated with 2013 SIMCE and with 2017 PSU and, with 2013 PSU outcomes in school-age children from 2010 5ESG and 1HSG, respectively. These findings may be useful for educational and health planning in Chile and countries in a comparable stage of development.

Beta oscillations precede joint attention and correlate with mentalization in typical development and autism.

A precursor of adult social functioning is joint attention (JA), which is the capacity to share attention on an object with another person. JA precedes the development of the capacity to attribute mental states to others (i.e., mentalization or theory of mind). The neural mechanisms involved in the development of mentalization are not fully understood. Electroencephalographic recordings were made of children while they watched stimuli on a screen and their interaction with the experimenter was assessed. We tested whether neuronal activity preceding JA correlates with mentalization in typically developing (TD) children and whether this activity is impaired in children with autistic spectrum disorder (ASD) who evidence deficits in JA and mentalization skills. Both groups exhibited JA behavior with comparable frequency. TD children displayed a higher amplitude of negative central (Nc) event-related potential preceding JA behavior (∼500 msec after stimuli presentation), than did the ASD group. Previous to JA behavior, TD children demonstrated beta oscillatory activity in the temporoparietal region, while ASD children did not show an increase in beta activity. In both groups, the beta power correlated with mentalization, suggesting that this specific neuronal mechanism is involved in mentalization, which used during social interaction.

Impact of anthropometric nutritional parameters on the university selection test in Chile: A multifactorial approach.

OBJECTIVES: Scholastic achievement (SA) is a multifactorial problem that depends on factors related to the child, the child's family, and the educational system. The aim of this study was to quantify the relative impact of significant variables at the beginning of high school during 2010 (first grade of high school [1 HSG]) on 2013 university selection test (Prueba de Seleccion Universitaria [PSU]) outcomes, both in language scholastic achievement (LSA) and mathematics scholastic achievement (MSA), when students graduated from high school (4 HSG). This was done at the time of university admission with a multicausal approach. The purpose was to confirm the hypothesis that the level of educational establishment SA, intellectual ability, sex, parental schooling levels, and head circumference for age Z-score at the onset of high school are the most relevant parameters associated with 2013 PSU outcomes, both in LSA and MSA. METHODS: A representative, proportional, and stratified sample of 671 children of both sexes who enrolled in 1 HSG in 2010 (mean age: 14.8 ± 0.6 y) participated in the study. Nutritional, intellectual, brain developmental, cardiovascular risk, socio-to-economic, demographic, and educational variables were quantitated. SA was assessed at 4 HSG with the 2013 PSU tests. Data were analyzed with SAS software. RESULTS: Educational establishment SA, intellectual ability, maternal schooling, and age Z-score were the most relevant parameters to explain LSA (R2 = 0.493; P < 0.0001) and MSA variance in addition to sex (male), but only in MSA (R2 = 0.600; P < 0.0001). CONCLUSIONS: These findings confirm the hypothesis and can be useful to support nutritional, health, and educational planning.

Docosahexaenoic acid levels in erythrocytes and their association with the University Selection Test Outcomes in Chile.

The aim of this study was to quantitate the relative impact of DHA and AA levels in erythrocytes, anthropometric parameters and socio-economic status of school-age children, of both genders, graduated from high school in Chile, on the scholastic achievement in the University Selection Test (Prueba de Selección Universitaria, PSU) both language scholastic achievement (LSA) and mathematics scholastic achievement (MSA). A representative sample of 671 school-age young graduated from high school in 2013, 550 and 548 of them took the PSU for LSA and MSA, respectively. Only school-age young with high (n = 91) and low (n = 69) SA in both tests were considered. A total of 122 school-age children agreed to participate in the study and were divided as follows: Group 1: high PSU outcome (n = 70; males n = 48) and Group 2: low PSU outcome (n = 52; males n = 23). Data were analyzed by means of SAS software. Independently of gender, DHA, socio-economic status and head circumference-for-age Z-score were the most relevant parameters explaining both LSA (R2 = 0.650; p < 0.0001) and MSA outcomes (R2 = 0.700; p < 0.0001). These results can be useful for nutrition, health and education planning, in order to protect children starting from an early age and thus increase their school outcomes.