A real-time fMRI neurofeedback system for the clinical alleviation of depression with a subject-independent classification of brain states: A proof of principle study.

Most clinical neurofeedback studies based on functional magnetic resonance imaging use the patient's own neural activity as feedback. The objective of this study was to create a subject-independent brain state classifier as part of a real-time fMRI neurofeedback (rt-fMRI NF) system that can guide patients with depression in achieving a healthy brain state, and then to examine subsequent clinical changes. In a first step, a brain classifier based on a support vector machine (SVM) was trained from the neural information of happy autobiographical imagery and motor imagery blocks received from a healthy female participant during an MRI session. In the second step, 7 right-handed female patients with mild or moderate depressive symptoms were trained to match their own neural activity with the neural activity corresponding to the "happiness emotional brain state" of the healthy participant. The training (4 training sessions over 2 weeks) was carried out using the rt-fMRI NF system guided by the brain-state classifier we had created. Thus, the informative voxels previously obtained in the first step, using SVM classification and Effect Mapping, were used to classify the Blood-Oxygen-Level Dependent (BOLD) activity of the patients and converted into real-time visual feedback during the neurofeedback training runs. Improvements in the classifier accuracy toward the end of the training were observed in all the patients [Session 4-1 Median = 6.563%; Range = 4.10-27.34; Wilcoxon Test (0), 2-tailed p = 0.031]. Clinical improvement also was observed in a blind standardized clinical evaluation [HDRS CE2-1 Median = 7; Range 2 to 15; Wilcoxon Test (0), 2-tailed p = 0.016], and in self-report assessments [BDI-II CE2-1 Median = 8; Range 1-15; Wilcoxon Test (0), 2-tailed p = 0.031]. In addition, the clinical improvement was still present 10 days after the intervention [BDI-II CE3-2_Median = 0; Range -1 to 2; Wilcoxon Test (0), 2-tailed p = 0.50/ HDRS CE3-2 Median = 0; Range -1 to 2; Wilcoxon Test (0), 2-tailed p = 0.625]. Although the number of participants needs to be increased and a control group included to confirm these findings, the results suggest a novel option for neural modulation and clinical alleviation in depression using noninvasive stimulation technologies.

Weighted neurofeedback facilitates greater self-regulation of functional connectivity between the primary motor area and cerebellum.

Objective.Brain-computer interface (BCI) is a tool that can be used to train brain self-regulation and influence specific activity patterns, including functional connectivity, through neurofeedback. The functional connectivity of the primary motor area (M1) and cerebellum play a critical role in motor recovery after a brain injury, such as stroke. The objective of this study was to determine the feasibility of achieving control of the functional connectivity between M1 and the cerebellum in healthy subjects. Additionally, we aimed to compare the brain self-regulation of two different feedback modalities and their effects on motor performance.Approach.Nine subjects were trained with a real-time functional magnetic resonance imaging BCI system. Two groups were conformed: equal feedback group (EFG), which received neurofeedback that weighted the contribution of both regions of interest (ROIs) equally, and weighted feedback group (WFG) that weighted each ROI differentially (30% cerebellum; 70% M1). The magnitude of the brain activity induced by self-regulation was evaluated with the blood-oxygen-level-dependent (BOLD) percent change (BPC). Functional connectivity was assessed using temporal correlations between the BOLD signal of both ROIs. A finger-tapping task was included to evaluate the effect of brain self-regulation on motor performance.Main results.A comparison between the feedback modalities showed that WFG achieved significantly higher BPC in M1 than EFG. The functional connectivity between ROIs during up-regulation in WFG was significantly higher than EFG. In general, both groups showed better tapping speed in the third session compared to the first. For WFG, there were significant correlations between functional connectivity and tapping speed.Significance.The results show that it is possible to train healthy individuals to control M1-cerebellum functional connectivity with rtfMRI-BCI. Besides, it is also possible to use a weighted feedback approach to facilitate a higher activity of one region over another.

Restoration of Vitamin D Levels Improves Endothelial Function and Increases TASK-Like K+ Currents in Pulmonary Arterial Hypertension Associated with Vitamin D Deficiency.

Background: Vitamin D (vitD) deficiency is highly prevalent in patients with pulmonary arterial hypertension (PAH). Moreover, PAH-patients with lower levels of vitD have worse prognosis. We hypothesize that recovering optimal levels of vitD in an animal model of PAH previously depleted of vitD improves the hemodynamics, the endothelial dysfunction and the ionic remodeling. Methods: Male Wistar rats were fed a vitD-free diet for five weeks and then received a single dose of Su5416 (20 mg/Kg) and were exposed to vitD-free diet and chronic hypoxia (10% O2) for three weeks to induce PAH. Following this, vitD deficient rats with PAH were housed in room air and randomly divided into two groups: (a) continued on vitD-free diet or (b) received an oral dose of 100,000 IU/Kg of vitD plus standard diet for three weeks. Hemodynamics, pulmonary vascular remodeling, pulmonary arterial contractility, and K+ currents were analyzed. Results: Recovering optimal levels of vitD improved endothelial function, measured by an increase in the endothelium-dependent vasodilator response to acetylcholine. It also increased the activity of TASK-1 potassium channels. However, vitD supplementation did not reduce pulmonary pressure and did not ameliorate pulmonary vascular remodeling and right ventricle hypertrophy. Conclusions: Altogether, these data suggest that in animals with PAH and severe deficit of vitD, restoring vitD levels to an optimal range partially improves some pathophysiological features of PAH.

Use of Real-Time Functional Magnetic Resonance Imaging-Based Neurofeedback to Downregulate Insular Cortex in Nicotine-Addicted Smokers.

It has been more than a decade since the first functional magnetic resonance imaging (fMRI)-based neurofeedback approach was successfully implemented. Since then, various studies have demonstrated that participants can learn to voluntarily control a circumscribed brain region. Consequently, real-time fMRI (rtfMRI) provided a novel opportunity to study modifications of behavior due to manipulation of brain activity. Hence, reports of rtfMRI applications to train self-regulation of brain activity and the concomitant modifications in behavioral and clinical conditions such as neurological and psychiatric disorders [e.g., schizophrenia, obsessive compulsive Disorder (OCD), stroke] have rapidly increased. Neuroimaging studies in addiction research have shown that the anterior cingulate cortex, orbitofrontal cortex, and insular cortex are activated during the presentation of drug-associated cues. Also, activity in both left and right insular cortices have been shown to be highly correlated with drug urges when participants are exposed to craving-eliciting cues. Hence, the bilateral insula is of particular importance in researching drug urges and addiction due to its role in the representation of bodily (interoceptive) states. This study explores the use of rtfMRI neurofeedback for the reduction in blood oxygen-level dependent (BOLD) activity in bilateral insular cortices of nicotine-addicted participants. The study also tests if there are neurofeedback training-associated modifications in the implicit attitudes of participants towards nicotine-craving cues and explicit-craving behavior.

Comunicación Intercultural como práctica para el rescate de conocimientos y sabidurías agropecuarias del Pueblo Mestizo / Intercultural Communication as a practice for the rescue of agricultural knowledge and wisdom of the mestizo people

Este artículo discute aspectos esenciales de la comunicación intercultural dialógica intergeneracional como práctica para el rescate de conocimientos y sabidurías ancestrales en la producción agropecuaria del pueblo mestizo de Siuna Región Autónoma de la Costa Caribe Norte de Nicaragua (RACCN). Las técnicas utilizadas en el estudio son el conversatorio, los grupos focales y la observación. Las personas involucradas fueron líderes comunitarios mestizos, abuelas, abuelos, jóvenes, hombres y mujeres de Siuna, que viven en las comunidades ubicadas en la vía hacia Waslala, Rosita y Mulukukú. El procesamiento de los datos cualitativos fue posible a la codificación de categorías y comparaciones entre los grupos auxiliados en el uso de matrices y triangulación de la información. El planteamiento de fondo de este estudio evidencia que la población mestiza posee expresiones y formas de comunicación que son propias y practicadas desde su cosmovisión asegurando trasmitir saberes y conocimientos en la producción agropecuaria.

This article discusses essential aspects of intergenerational intercultural dialogic communication as a practice for the rescue of ancestral knowledge and wisdom in the agricultural production of the mestizo people from Siuna, Autonomous Region of the North Caribbean Coast of Nicaragua (RACCN). The techniques used in the study were conversation, focus groups and observation. The people involved were mestizo community leaders, grandparents, youth, men and women from Siuna, who live in the communities located on the road to Waslala, Rosita and Mulukukú. The qualitative data processing was possible to codify categories and comparisons between the groups assisted in the use of matrices and triangulation of information. The underlying approach of this study shows that the mestizo population has expressions and forms of communication that are their own and practiced from their worldview ensuring that they transmit knowledge and knowledge in agricultural production.

Learned control of inter-hemispheric connectivity: Effects on bimanual motor performance.

Bimanual movements involve the interactions between both primary motor cortices. These interactions are assumed to involve phase-locked oscillatory brain activity referred to as inter-hemispheric functional coupling. So far, inter-hemispheric functional coupling has been investigated as a function of motor performance. These studies report mostly a negative correlation between the performance in motor tasks and the strength of functional coupling. However, correlation might not reflect a causal relationship. To overcome this limitation, we opted for an alternative approach by manipulating the strength of inter-hemispheric functional coupling and assessing bimanual motor performance as a dependent variable. We hypothesize that an increase/decrease of functional coupling deteriorates/facilitates motor performance in an out-of-phase bimanual finger-tapping task. Healthy individuals were trained to volitionally regulate functional coupling in an operant conditioning paradigm using real-time magnetoencephalography neurofeedback. During operant conditioning, two discriminative stimuli were associated with upregulation and downregulation of functional coupling. Effects of training were assessed by comparing motor performance prior to (pre-test) and after the training (post-test). Participants receiving contingent feedback learned to upregulate and downregulate functional coupling. Comparing motor performance, as indexed by the ratio of tapping speed for upregulation versus downregulation trials, no change was found in the control group between pre- and post-test. In contrast, the group receiving contingent feedback evidenced a significant decrease of the ratio implicating lower tapping speed with stronger functional coupling. Results point toward a causal role of inter-hemispheric functional coupling for the performance in bimanual tasks. Hum Brain Mapp 38:4353-4369, 2017. © 2017 Wiley Periodicals, Inc.

How feedback, motor imagery, and reward influence brain self-regulation using real-time fMRI.

The learning process involved in achieving brain self-regulation is presumed to be related to several factors, such as type of feedback, reward, mental imagery, duration of training, among others. Explicitly instructing participants to use mental imagery and monetary reward are common practices in real-time fMRI (rtfMRI) neurofeedback (NF), under the assumption that they will enhance and accelerate the learning process. However, it is still not clear what the optimal strategy is for improving volitional control. We investigated the differential effect of feedback, explicit instructions and monetary reward while training healthy individuals to up-regulate the blood-oxygen-level dependent (BOLD) signal in the supplementary motor area (SMA). Four groups were trained in a two-day rtfMRI-NF protocol: GF with NF only, GF,I with NF + explicit instructions (motor imagery), GF,R with NF + monetary reward, and GF,I,R with NF + explicit instructions (motor imagery) + monetary reward. Our results showed that GF increased significantly their BOLD self-regulation from day-1 to day-2 and GF,R showed the highest BOLD signal amplitude in SMA during the training. The two groups who were instructed to use motor imagery did not show a significant learning effect over the 2 days. The additional factors, namely motor imagery and reward, tended to increase the intersubject variability in the SMA during the course of training. Whole brain univariate and functional connectivity analyses showed common as well as distinct patterns in the four groups, representing the varied influences of feedback, reward, and instructions on the brain. Hum Brain Mapp 37:3153-3171, 2016. © 2016 Wiley Periodicals, Inc.

Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs.

Fanconi anaemia (FA) is a recessive disorder characterized by genomic instability, congenital abnormalities, cancer predisposition and bone marrow (BM) failure. However, the pathogenesis of FA is not fully understood partly due to the limitations of current disease models. Here, we derive integration free-induced pluripotent stem cells (iPSCs) from an FA patient without genetic complementation and report in situ gene correction in FA-iPSCs as well as the generation of isogenic FANCA-deficient human embryonic stem cell (ESC) lines. FA cellular phenotypes are recapitulated in iPSCs/ESCs and their adult stem/progenitor cell derivatives. By using isogenic pathogenic mutation-free controls as well as cellular and genomic tools, our model serves to facilitate the discovery of novel disease features. We validate our model as a drug-screening platform by identifying several compounds that improve hematopoietic differentiation of FA-iPSCs. These compounds are also able to rescue the hematopoietic phenotype of FA patient BM cells.

Real-time fMRI brain computer interfaces: self-regulation of single brain regions to networks.

With the advent of brain computer interfaces based on real-time fMRI (rtfMRI-BCI), the possibility of performing neurofeedback based on brain hemodynamics has become a reality. In the early stage of the development of this field, studies have focused on the volitional control of activity in circumscribed brain regions. However, based on the understanding that the brain functions by coordinated activity of spatially distributed regions, there have recently been further developments to incorporate real-time feedback of functional connectivity and spatio-temporal patterns of brain activity. The present article reviews the principles of rtfMRI neurofeedback, its applications, benefits and limitations. A special emphasis is given to the discussion of novel developments that have enabled the use of this methodology to achieve self-regulation of the functional connectivity between different brain areas and of distributed brain networks, anticipating new and exciting applications for cognitive neuroscience and for the potential alleviation of neuropsychiatric disorders.

Learned regulation of brain metabolism.

Self-regulation and voluntary control of circumscribed brain regions using real-time functional MRI (rt-fMRI) allows the establishment of a causal functional link between localized brain activity and behavior and cognition. A long tradition of research has clearly shown the brain's ability to learn volitional control of its own activity and effects on behavior. Yet, the underlying neural mechanism of self-regulation is still not fully understood. Here, we propose that self-regulation of brain activity is akin to skill learning and thus may depend on an intact subcortical motor system. We elaborate on the critical role of the basal ganglia in skill learning and neurofeedback, and clarify that brain-self-regulation need not be an explicit and conscious process as often mistakenly held.

Acquired self-control of insula cortex modulates emotion recognition and brain network connectivity in schizophrenia.

Real-time functional magnetic resonance imaging (rtfMRI) is a novel technique that has allowed subjects to achieve self-regulation of circumscribed brain regions. Despite its anticipated therapeutic benefits, there is no report on successful application of this technique in psychiatric populations. The objectives of the present study were to train schizophrenia patients to achieve volitional control of bilateral anterior insula cortex on multiple days, and to explore the effect of learned self-regulation on face emotion recognition (an extensively studied deficit in schizophrenia) and on brain network connectivity. Nine patients with schizophrenia were trained to regulate the hemodynamic response in bilateral anterior insula with contingent rtfMRI neurofeedback, through a 2-weeks training. At the end of the training stage, patients performed a face emotion recognition task to explore behavioral effects of learned self-regulation. A learning effect in self-regulation was found for bilateral anterior insula, which persisted through the training. Following successful self-regulation, patients recognized disgust faces more accurately and happy faces less accurately. Improvements in disgust recognition were correlated with levels of self-activation of right insula. RtfMRI training led to an increase in the number of the incoming and outgoing effective connections of the anterior insula. This study shows for the first time that patients with schizophrenia can learn volitional brain regulation by rtfMRI feedback training leading to changes in the perception of emotions and modulations of the brain network connectivity. These findings open the door for further studies of rtfMRI in severely ill psychiatric populations, and possible therapeutic applications.

Generation of a drug-inducible reporter system to study cell reprogramming in human cells.

BACKGROUND: Strategies on the basis of doxycycline-inducible lentiviruses in mouse cells allowed the examination of mechanisms governing somatic cell reprogramming. RESULTS: Using a doxycycline-inducible human reprogramming system, we identified unreported miRs enhancing reprogramming efficiency. CONCLUSION: We generated a drug-inducible human reprogramming reporter system as an invaluable tool for genetic or chemical screenings. SIGNIFICANCE: These cellular systems provide a tool to enable the advancement of reprogramming technologies in human cells. Reprogramming of somatic cells into induced pluripotent stem cells is achieved by the expression of defined transcription factors. In the last few years, reprogramming strategies on the basis of doxycycline-inducible lentiviruses in mouse cells became highly powerful for screening purposes when the expression of a GFP gene, driven by the reactivation of endogenous stem cell specific promoters, was used as a reprogramming reporter signal. However, similar reporter systems in human cells have not been generated. Here, we describe the derivation of drug-inducible human fibroblast-like cell lines that express different subsets of reprogramming factors containing a GFP gene under the expression of the endogenous OCT4 promoter. These cell lines can be used to screen functional substitutes for reprogramming factors or modifiers of reprogramming efficiency. As a proof of principle of this system, we performed a screening of a library of pluripotent-enriched microRNAs and identified hsa-miR-519a as a novel inducer of reprogramming efficiency.

Detection of cerebral reorganization induced by real-time fMRI feedback training of insula activation: a multivariate investigation.

BACKGROUND: Studies with real-time functional magnetic resonance imaging (fMRI) demonstrate that humans volitionally regulate hemodynamic signals from circumscribed regions of the brain, leading to area-specific behavioral consequences. Methods to better determine the nature of dynamic functional interactions between different brain regions and plasticity due to self-regulation training are still in development. OBJECTIVE: The authors investigated changes in brain states while training 6 healthy participants to self-regulate insular cortex by real-time fMRI feedback. METHOD: The authors used multivariate pattern analysis to observe spatial pattern changes and a multivariate Granger causality model to show changes in temporal interactions in multiple brain areas over the course of 5 repeated scans per subject during positive and negative emotional imagery with feedback about the level of insular activation. RESULTS: Feedback training leads to more spatially focused recruitment of areas relevant for learning and emotion. Effective connectivity analysis reveals that initial training is associated with an increase in network density; further training "prunes" presumably redundant connections and "strengthens" relevant connections. CONCLUSIONS: The authors demonstrate the application of multivariate methods for assessing cerebral reorganization during the learning of volitional control of local brain activity. The findings provide insight into mechanisms of training-induced learning techniques for rehabilitation. The authors anticipate that future studies, specifically designed with this hypothesis in mind, may be able to construct a universal index of cerebral reorganization during skill learning based on multiple similar criteria across various skilled tasks. These techniques may be able to discern recovery from compensation, dose-response curves related to training, and ways to determine whether rehabilitation training is actively engaging necessary networks.

Estrés, calidad de vida y psoriasis: estado actual / Stress, quality of life and psoriasis: current status

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