Correction: Epigenetic, psychological, and EEG changes after a 1-week retreat based on mindfulness and compassion for stress reduction in healthy adults: Study protocol of a cross-over randomized controlled trial.

[This corrects the article DOI: 10.1371/journal.pone.0283169.].

Epigenetic, psychological, and EEG changes after a 1-week retreat based on mindfulness and compassion for stress reduction in healthy adults: Study protocol of a cross-over randomized controlled trial.

INTRODUCTION: The main objective of the study will be to evaluate the effects of two widely used standardized mindfulness-based programs [Mindfulness-Based Stress Reduction (MBSR) and Compassion Cultivation Training (CCT)], on epigenetic, neurobiological, psychological, and physiological variables. METHODS: The programs will be offered in an intensive retreat format in a general population sample of healthy volunteer adults. During a 7-day retreat, participants will receive MBSR and CCT in a crossover design where participants complete both programs in random order. After finishing their first 3-day training with one of the two programs, participants will be assigned to the second 3-day training with the second program. The effects of the MBSR and CCT programs, and their combination, will be measured by epigenetic changes (i.e., DNA methylation biomarkers), neurobiological and psychophysiological measures (i.e., EEG resting state, EKG, respiration patterns, and diurnal cortisol slopes), self-report questionnaires belonging to different psychological domains (i.e., mindfulness, compassion, well-being, distress, and general functioning), and stress tasks (i.e., an Arithmetic Stress Test and the retrieval of negative autobiographical memories). These measures will be collected from both groups on the mornings of day 1 (pre-program), day 4 (after finishing the first program and before beginning the second program), and day 7 (post-second program). We will conduct a 3-month and a 12-month follow-up using only the set of self-report measures. DISCUSSION: This study aims to shed light on the neurobiological and psychological mechanisms linked to meditation and compassion in the general population. The protocol was registered at clinicaltrials.gov (Identifier: NCT05516355; August 23, 2022).

The effectiveness of a school mindfulness-based intervention on the neural correlates of inhibitory control in children at risk: A randomized control trial.

Interest in the applications of mindfulness practice in education is growing in the scientific community. Recent research has shown that mindfulness practice in schools may be beneficial for executive functions (EFs) which are abilities crucial for healthy development. The study of the effects of mindfulness practices on children's neural correlates of EFs, particularly inhibitory control, may provide relevant information about the impact and mechanisms of mindfulness-based interventions (MBIs) in children. The aim of the present study was to investigate the effects of a MBI in elementary school children on the neural correlates of inhibitory control via a randomized controlled trial. Children from two 4th grade classrooms and two 5th grade classrooms located in a school identified as having low socioeconomic status in Santiago de Chile were randomly assigned to either receive a MBI or serve as active controls and receive a social skills program. Both before and after the interventions, electroencephalographic activity was recorded during a modified version of the Go/Nogo task in a subsample of children in each group. Additionally, teachers completed questionnaires of students' EFs and students completed self-report measures. Results revealed increases in EFs assessed by questionnaires together with improved P3 amplitude associated with successful response inhibition in children who received the MBI compared to active controls. These results contribute to the understanding of the ways in which mindfulness practices can promote the development of inhibitory control together with EF improvement, factors identified as critical for children's social and emotional development and positive mental health. RESEARCH HIGHLIGHTS: This study investigated the effects of a mindfulness-based intervention in children from a low socioeconomic status school on neural correlates of EFs. Children performed a Go/Nogo task while electroencephalographic activity was recorded and completed questionnaires before and after a MBI or an active control program. Improvements in EFs assessed by questionnaires together with an increased Nogo-P3 activity associated with successful inhibition in children who received the MBI were found. The results could contribute to understand how mindfulness practice can promote the development of inhibitory control in children from vulnerable populations.

Efficacy of mindfulness to regulate induced emotions in the laboratory: A systematic review and meta-analysis of self-report and biobehavioral measures.

A substantial part of the research on the efficacy of mindfulness-based interventions on mood regulation is conducted in the laboratory. Nevertheless, a systematic review of the results is lacking. This meta-analysis aimed to investigate the effects of mindfulness as an emotion regulation (ER) strategy when using mood induction procedures. A systematic search of databases was conducted and a total of 43 studies were included in the meta-analysis. We found a small significant overall effect size of mindfulness [g= -0.15 (95% CI [-0.30, -0.01], p = 0.04)], which became non-significant after removing outliers (g=-0.15, p = 0.06). We also found high levels of heterogeneity which was not explained by the moderating variables analyzed. Thus, there is limited meta-analytic evidence of the efficacy of mindfulness strategies in down-regulating or preventing heightened or chronic effects of induced mood states in well-controlled laboratory settings. We propose that this could be partially due to some limitations in laboratory methodologies and suggest some guidelines to overcome them in future primary research.

Enhanced response inhibition and reduced midfrontal theta activity in experienced Vipassana meditators.

Response inhibition - the ability to suppress inappropriate thoughts and actions - is a fundamental aspect of cognitive control. Recent research suggests that mental training by meditation may improve cognitive control. Yet, it is still unclear if and how, at the neural level, long-term meditation practice may affect (emotional) response inhibition. The present study aimed to address this outstanding question, and used an emotional Go/Nogo task and electroencephalography (EEG) to examine possible differences in behavioral and electrophysiological indices of response inhibition between Vipassana meditators and an experience-matched active control group (athletes). Behaviorally, meditators made significantly less errors than controls on the emotional Go/Nogo task, independent of the emotional context, while being equally fast. This improvement in response inhibition at the behavioral level was accompanied by a decrease in midfrontal theta activity in Nogo vs. Go trials in the meditators compared to controls. Yet, no changes in ERP indices of response inhibition, as indexed by the amplitude of the N2 and P3 components, were observed. Finally, the meditators subjectively evaluated the emotional pictures lower in valence and arousal. Collectively, these results suggest that meditation may improve response inhibition and control over emotional reactivity.

Effects of a brief mindfulness-meditation intervention on neural measures of response inhibition in cigarette smokers.

Research suggests that mindfulness-practices may aid smoking cessation. Yet, the neural mechanisms underlying the effects of mindfulness-practices on smoking are unclear. Response inhibition is a main deficit in addiction, is associated with relapse, and could therefore be a candidate target for mindfulness-based practices. The current study hence investigated the effects of a brief mindfulness-practice on response inhibition in smokers using behavioral and electroencephalography (EEG) measures. Fifty participants (33 females, mean age 20 years old) underwent a protocol of cigarette exposure to induce craving (cue-exposure) and were then randomly assigned to a group receiving mindfulness-instructions or control-instructions (for 15 minutes approximately). Immediately after this, they performed a smoking Go/NoGo task, while their brain activity was recorded. At the behavioral level, no group differences were observed. However, EEG analyses revealed a decrease in P3 amplitude during NoGo vs. Go trials in the mindfulness versus control group. The lower P3 amplitude might indicate less-effortful response inhibition after the mindfulness-practice, and suggest that enhanced response inhibition underlies observed positive effects of mindfulness on smoking behavior.

ALS-linked protein disulfide isomerase variants cause motor dysfunction.

Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease.

Functional Role of the Disulfide Isomerase ERp57 in Axonal Regeneration.

ERp57 (also known as grp58 and PDIA3) is a protein disulfide isomerase that catalyzes disulfide bonds formation of glycoproteins as part of the calnexin and calreticulin cycle. ERp57 is markedly upregulated in most common neurodegenerative diseases downstream of the endoplasmic reticulum (ER) stress response. Despite accumulating correlative evidence supporting a neuroprotective role of ERp57, the contribution of this foldase to the physiology of the nervous system remains unknown. Here we developed a transgenic mouse model that overexpresses ERp57 in the nervous system under the control of the prion promoter. We analyzed the susceptibility of ERp57 transgenic mice to undergo neurodegeneration. Unexpectedly, ERp57 overexpression did not affect dopaminergic neuron loss and striatal denervation after injection of a Parkinson's disease-inducing neurotoxin. In sharp contrast, ERp57 transgenic animals presented enhanced locomotor recovery after mechanical injury to the sciatic nerve. These protective effects were associated with enhanced myelin removal, macrophage infiltration and axonal regeneration. Our results suggest that ERp57 specifically contributes to peripheral nerve regeneration, whereas its activity is dispensable for the survival of a specific neuronal population of the central nervous system. These results demonstrate for the first time a functional role of a component of the ER proteostasis network in peripheral nerve regeneration.

The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein.

Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.

Protein disulfide isomerases in neurodegeneration: from disease mechanisms to biomedical applications.

Protein disulfide isomerases (PDIs) are a family of foldases and chaperones primarily located at the endoplasmic reticulum that catalyze the formation and isomerization of disulfide bonds thereby facilitating protein folding. PDIs also perform important physiological functions in protein quality control, cell death, and cell signaling. Protein misfolding is involved in the etiology of the most common neurodegenerative diseases, including Alzheimer, Parkinson, amyotrophic lateral sclerosis, Prion-related disorders, among others. Accumulating evidence indicate altered expression of PDIs as a prominent and common feature of these neurodegenerative conditions. Here we overview most recent advances in our understanding of the possible functional contribution of PDIs to neurodegeneration, depicting a complex and poorly understood scenario. Possible therapeutic benefits of targeting PDIs in a disease context and their use as biomarkers are discussed.