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Effects of Mindfulness-Based Stress Prevention on Serotonin Transporter Gene Methylation
Abstract
Received: March 19, 2019
Accepted: June 22, 2019
Published online: August 28, 2019
Issue release date: September 2019
... Although there is little scientific literature referring to MEN as an integrated approach, there is one study that examined its use in breast-cancer survivors. However, the study did not include a biological link that explains the benefits [16] or show the biological effect alone, and it did not include any specific guidelines about diet and exercise [17]. In terms of diet, we acknowledge the MD as being defined as a sustainable diet. ...
... Another study has shown that methylation in a CpG island (correlated with silencing of genes) in the 5 region of the 5HTT gene, has been associated with a decrease in gene expression which, under stressful conditions, would induce changes in behavioral response [64]. Moreover, the postintervention mindfulness-program (MP) has shown that it can contribute to the reduction of gene methylation with a "preventive" effect on the onset of psychological stress [17]. ...
Over the past two years, the world's population has been tested by the COVID-19 health emergency. This has changed population habits worldwide by encouraging a sedentary lifestyle and overnutrition. Isolation and reduction of social life, for most of the population, was mandatory but it quickly became a new lifestyle. Nowadays, we are encountering the consequences with an increase in nutritional associated disorders and conditions that cause illnesses in the general population. These disorders include diet excesses that lead to obesity and diet deficiencies and malnutrition which could rapidly lead to death. These eating disorders are very complex to manage because they become mental disorders which can negatively impact physical or mental health. This work will disucss the benefits associated with the mindfulness-exercise-nutrition (MEN) technique. From a nutritional point of view it will focus on the nutritional effect of a plant-based diet, such as the Mediterranean diet (MD) which has a high tryptophan content which can increase serotonin (the "feel good" hormone) levels. The MEN technique takes a multidisciplinary approach and aims to integrate healthy behaviors into clinical practice using healthy eating, active living, and mindfulness. This method includes controlled physical movements, stretching techniques such as yoga, and aerobic exercise to achieve optimal mental and physical health. This literature review, carried out using the PubMed, ScienceDirect, Scopus, and Google Scholar databases, aims to investigate the latest research on this topic. This study may be useful for healthcare professionals and clinicians and may help patients to be more self-aware, encouraging them to lead a healthier lifestyle, make thoughtful choices, and ameliorate their mental health. The final aim of this study is to promote physiological homeostasis and well-being.
... Environmental factors may have an effect on the development, course, and treatment of diseases via epigenetic mechanisms (e.g., [18,19]). Epigenetic mechanisms describe a series of biochemical processes that can alter the phenotype of an individual without altering the DNA sequence. ...
... Methylation levels can also be altered by interventions such as alcohol withdrawal [29] and psychotherapy for stress prevention [19], thus giving insight into the molecular epigenetic mechanisms underlying therapy response. ...
Purpose of Review
In this study, we illustrate recent findings regarding the genetics and epigenetics of alcohol use disorder (AUD). We further outline the future direction of genetic and epigenetic research in AUD.
Recent Findings
Recent genome- and epigenome-wide studies allow new insight into genetic and epigenetic variation associated with AUD. The largest EWAS of AUD so far/to date found evidence for altered glucocorticoid receptor regulation. Longitudinal studies provide insight into the dynamics of the disease. Analyses of postmortem brain tissue reveal the impact of chronic alcohol consumption on DNA methylation in the brain.
Summary
Genetic and environmental factors—mediated via epigenetic mechanisms—play an important role in AUD. Although knowledge of the biological underpinnings of AUD is still limited, ongoing research will ultimately lead to the development of biomarkers for disease classification, course of disease, and treatment response to support personalized medicine in the future.
... A recent study on the effect of a mindfulness-based preventive intervention in medical students preparing for a stressful exam, however, the effectiveness of the preventive measure, i.e. stress reduction, went along with a decrease in SLC6A4 methylation (Stoffel et al., 2019). ...
... In light of the recently burgeoning body of research into the potential of epigenetic modifications to predict mental disorder risk and treatment outcome as well as of psychotherapeutic interventions to target -and potentially reverse -epigenetic risk patterns as reviewed above, this direction carries great promise for preventive interventions to potentially compensate for putative vulnerability factors precipitating mental disorder onset -or to strengthen factors and resources associated with resilient functioning (see Fig. 2). First promising evidence in this regard emerges from a study showing response to a mindfulness-based preventive intervention to go along with decreasing SLC6A4 methylation (Stoffel et al., 2019) as well as studies reporting reduced harsh parenting conferred by a family-centered prevention training or the presence of supportive family environments despite racial discrimination to protect against accelerated epigenetic aging. Future studies are warranted to investigate the malleability of epigenetic risk patterns by preventive interventions more thoroughly in analogy to therapy-epigenetic research. ...
Mental disorders are highly complex and multifactorial in origin, comprising an elaborate interplay of genetic and environmental factors. Epigenetic mechanisms such as DNA modifications (e.g. CpG methylation), histone modifications (e.g. acetylation) and microRNAs function as a translator between genes and the environment. Indeed, environmental influences such as exposure to stress shape epigenetic patterns, and lifetime experiences continue to alter the function of the genome throughout the lifespan. Here, we summarize the recently burgeoning body of research regarding the involvement of aberrant epigenetic signatures in mediating an increased vulnerability to a wide range of mental disorders. We review the current knowledge of epigenetic changes to constitute useful markers predicting the clinical response to psychotherapeutic interventions, and of psychotherapy to alter – and potentially reverse – epigenetic risk patterns. Given first evidence pointing to a transgenerational transmission of epigenetic information, epigenetic alterations arising from successful psychotherapy might be transferred to future generations and thus contribute to the prevention of mental disorders. Findings are integrated into a multi-level framework highlighting challenges pertaining to the mechanisms of action and clinical implications of epigenetic research. Promising future directions regarding the prediction, prevention, and personalized treatment of mental disorders in line with a ‘precision medicine’ approach are discussed.
... Evidence of higher levels of serotonin production has also been associated with mindfulness. Serotonin functions in the body to aid in regulating a person's mood and general well-being feelings [58,59]. On the other side, higher levels of BDNF have been related to increased cognitive functioning and emotional resilience [60][61][62]. ...
Background and Objectives: Meditation and mindfulness, rooted in ancient traditions, enhance mental well-being by cultivating awareness and emotional control. It has been shown to induce neuroplasticity, increase cortical thickness, reduce amygdala reactivity, and improve brain connectivity and neurotransmitter levels, leading to improved emotional regulation, cognitive function, and stress resilience. This systematic review will synthesize research on neurobiological changes associated with mindfulness and meditation practices. Materials and Methods: Studies were identified from an online search of PubMed, Web of Science, Cochrane Library, and Embase databases without any search time range. This review has been registered on Open OSF (n) GV2JY. Results: Mindfulness-Based Stress Reduction (MBSR) enhances brain regions related to emotional processing and sensory perception, improves psychological outcomes like anxiety and depression, and exhibits unique mechanisms of pain reduction compared to placebo. Conclusions: This review highlights that mindfulness, particularly through MBSR, improves emotional regulation and brain structure, reduces anxiety, and enhances stress resilience. Future research should focus on diverse populations and naturalistic settings to better understand and optimize these benefits.
... These two genes were chosen based on preliminary evidence from our prior study suggesting associations with MBSR response in PTSD [35]. Additional supporting evidence includes findings from studies of mindfulness-based stress prevention [36], cortisol stress reactivity [27,28], and relevance to HPA axis and serotonin signaling associated with meditation mechanisms [16][17][18][19]. These two genes are therefore unique in that they both have prior genotype and methylation associations with PTSD disease risk and response to interventions used for PTSD. ...
Meditation-based interventions are novel and effective non-pharmacologic treatments for veterans with PTSD. We examined relationships between treatment response, early life trauma exposure, DNA polymorphisms, and methylation in the serotonin transporter (SLC6A4) and FK506-binding protein 5 (FKBP5) genes. DNA samples and clinical outcomes were examined in 72 veterans with PTSD who received meditation-based therapy in two separate studies of mindfulness-based stress reduction (MBSR) and Transcendental Meditation (TM). The PTSD Checklist was administered to assess symptoms at baseline and after 9 weeks of meditation intervention. We examined the SLC6A4 promoter (5HTTLPR_L/S insertion/deletion + rs25531_A/G) polymorphisms according to previously defined gene expression groups, and the FKBP5 variant rs1360780 previously associated with PTSD disease risk. Methylation for CpG sites of SLC6A4 (28 sites) and FKBP5 (45 sites) genes was quantified in DNA samples collected before and after treatment. The 5HTTLPR LALA high expression genotype was associated with greater symptom improvement in participants exposed to early life trauma (p = 0.015). Separately, pre to post-treatment change of DNA methylation in a group of nine FKBP5 CpG sites was associated with greater symptom improvement (OR = 2.8, 95% CI 1.1–7.1, p = 0.027). These findings build on a wealth of existing knowledge regarding epigenetic and genetic relationships with PTSD disease risk to highlight the potential importance of SLC6A4 and FKBP5 for treatment mechanisms and as biomarkers of symptom improvement.
... Active controls comprised only in two (11%) studies CBT; otherwise, interventions such as cognitive control trainings, health enhancement programs, or relaxation trainings were used. Thirty-one of the 35 studies with a control group were RCTs; four were nonrandomized [76][77][78][79]. Seven studies (16%) conducted a follow-up assessment. ...
Mindfulness-based interventions (MBIs) have a positive effect on biomarkers of inflammation and stress in patients with psychiatric disorders and physical illnesses. Regarding subclinical populations, results are less clear. The present meta-analysis addressed the effects of MBIs on biomarkers in psychiatric populations and among healthy, stressed, and at-risk populations. All available biomarker data were investigated with a comprehensive approach, using two three-level meta-analyses. Pre–post changes in biomarker levels within treatment groups (k = 40 studies, total N = 1441) and treatment effects compared to control group effects, using only RCT data (k = 32, total N = 2880), were of similar magnitude, Hedges g = −0.15 (95% CI = [−0.23, −0.06], p < 0.001) and g = −0.11 (95% CI = [−0.23, 0.001], p = 0.053). Effects increased in magnitude when including available follow-up data but did not differ between type of sample, MBI, biomarker, and control group or duration of the MBI. This suggests that MBIs may ameliorate biomarker levels in both psychiatric and subclinical populations to a small extent. However, low study quality and evidence of publication bias may have impacted on the results. More large and preregistered studies are still needed in this field of research.
... There is a vast amount of literature on telomere length in relation to stress, aging, and meditation; therefore, this topic will not be further addressed in the present review. One interesting report found that following MBI sessions based on mindfulness meditation, breathing attention and body scan, DNAm levels from whole blood samples were reduced at the promoter of the SLC6A4 gene, which encodes a serotonin transporter (5-HTT) that catalyzes serotonin reuptake from the synaptic cleft (Stoffel et al., 2019). SLC6A4 was shown to be hypermethylated in correlation with depression due to adverse life events (Bakusic et al., 2020) and hypermethylation was associated with orbitofrontal cortex (OFC) activation, greater OFC-Amygdala and Anterior Cingulate Cortex-Insula connectivity in conditions of negative emotions (sadness, fear; Ismaylova et al., 2018;Palma-Gudiel & Fañanás, 2017). ...
Many environmental and lifestyle related factors may influence the physiology of the brain and body by acting on fundamental molecular pathways, such as the hypothalamus-pituitary-adrenal axis (HPA) and the immune system. For example, stressful conditions created by adverse early-life events, unhealthy habits and low socio-economic status may favor the onset of diseases linked to neuroendocrine dysregulation, inflammation and neuroinflammation. Beside pharmacological treatments used in clinical settings, much attention has been given to complementary treatments such as mind-body techniques involving meditation that rely on the activation of inner resources to regain health. At the molecular level, the effects of both stress and meditation are elicited epigenetically through a set of mechanisms that regulate gene expression as well as the circulating neuroendocrine and immune effectors. Epigenetic mechanisms constantly reshape genome activities in response to external stimuli, representing a molecular interface between organism and environment. In the present work, we aimed to review the current knowledge on the correlation between epigenetics, gene expression, stress and its possible antidote, meditation. After introducing the relationship between brain, physiology, and epigenetics, we will proceed to describe three basic epigenetic mechanisms: chromatin covalent modifications, DNA methylation and non-coding RNAs. Subsequently, we will give an overview of the physiological and molecular aspects related to stress. Finally, we will address the epigenetic effects of meditation on gene expression. The results of the studies reported in this review demonstrate that mindful practices modulate the epigenetic landscape, leading to increased resilience. Therefore, these practices can be considered valuable tools that complement pharmacological treatments when coping with pathologies related to stress.
... However, it had no effect on HRV, whereas MBI, including Yoga, did. Furthermore, we found that MBI altered epigenetic serotonin transporter related mechanisms (Stoffel et al., 2019). ...
A large body of literature has shown the effectiveness of mindfulness-based interventions (MBI) on stress-reduction. However, little is known about their effects on psychobiological stress-markers in daily life through an ecological momentary assessment approach. Our study examines the effects of MBI on state mindfulness, perceived stress, and indicators of sympathetic-nervous-system (saliva alpha-amylase, sAA) and hypothalamic-pituitary-adrenal-axis (saliva cortisol, sCort) activation in daily life. Twenty-eight individuals participated in a three-month MBI (IG) and were compared to 46 controls (CG). An ecological momentary assessment (EMA) was used to assess mindfulness, stress, sAA and sCort at six measurements per day on two days each before and after the MBI. Multilevel-modeling was used to analyze the data on a moment-to-moment and averaged day-level. The IG showed decreased sAA levels (AUCg) from pre to post, while the CG showed increases. Furthermore, diurnal decreases in sCort (AUCi) were pronounced in the IG compared to the CG. On a momentary basis, mindfulness was associated with lower stress and sAA levels, but not sCort. As such, we show that MBI can reduce sympathetic and to a lesser extent hypothalamic-pituitary-adrenal activation in daily life. Increased mindfulness can momentarily decrease stress and stress-related autonomic activation with implications for health. Our results emphasize the importance of brief interventions that can be easily integrated into everyday life.
... For example, changes in DNA methylation of candidate stress-related genes (FKBP5, SLC6A4) have been observed in patients undergoing psychological treatments for PTSD, phobia, or anxiety symptoms. [64][65][66] In a more recent hypothesis-free epigenome-wide approach, treatment-responsive individuals exhibited reduction of PTSD symptoms alongside differential DNA methylation in multiple genes. 67 However, although epigenetic changes occur alongside symptom reduction, it is not clear whether the psychological therapies rectify the biological "scarring" of prior negative experiences or have their own independent promotive effect. ...
There is significant variation in the response to adversity, with a substantial proportion of individuals displaying psychological resilience. Epigenetic mechanisms are hypothesised to be one molecular pathway of how experiences can become biologically embedded and contribute to individual differences in resilience. However, not much is known regarding the role of epigenetics in the development of psychological resilience. In this review, we propose a new conceptual model for the different functions of epigenetic mechanisms in psychological resilience. The model considers 1) the initial establishment of the epigenome, 2) epigenetic modification due to protective environmental exposures across life, 3) the role of protective factors in counteracting adverse influences, and 4) genetic moderation of environmentally induced epigenetic modifications. After reviewing empirical evidence for the various components of the model, we identify research areas which should be prioritized and discuss practical implications of the proposed model for epigenetic research on resilience.
Epigenetic mechanisms are key processes that constantly reshape genome activity carrying out physiological responses to environmental stimuli. Such mechanisms regulate gene activity without modifying the DNA sequence, providing real-time adaptation to changing environmental conditions. Both favorable and unfavorable lifestyles have been shown to influence body and brain by means of epigenetics, leaving marks on the genome that can either be rapidly reversed or persist in time and even be transmitted trans-generationally. Among virtuous habits, meditation seemingly represents a valuable way of activating inner resources to cope with adverse experiences. While unhealthy habits, stress, and traumatic early-life events may favor the onset of diseases linked to inflammation, neuroinflammation, and neuroendocrine dysregulation, the practice of mindfulness-based techniques was associated with the alleviation of many of the above symptoms, underlying the importance of lifestyles for health and well-being. Meditation influences brain and body systemwide, eliciting structural/morphological changes as well as modulating the levels of circulating factors and the expression of genes linked to the HPA axis and the immune and neuroimmune systems. The current chapter intends to give an overview of pioneering research showing how meditation can promote health through epigenetics, by reshaping the profiles of the three main epigenetic markers, namely DNA methylation, histone modifications, and non-coding RNAs.
Objectives: Mindfulness-based interventions (MBIs) for persons with dementia (PwD) have yielded mixed results, possibly attributable to the fact that little is known about the validity and reliability of trait mindfulness self-report measures in PwD. This narrative review sought to identify studies involving self-reported trait mindfulness and other clinical measures that may hold information on the convergent validity and reliability of these measures in PwD.
Methods: Scientific databases were searched for studies involving PwD and mindfulness assessments.
Results: N = 426 studies from PubMed and N = 156 from PsychInfo databases were reviewed. Four cross-sectional studies were identified that allowed inferences about the validity of mindfulness measures. A qualitative review indicated that convergent validity with other measures varied with sample heterogeneity and cognitive impairment. Merely one MBI included self-reported trait mindfulness, however without reporting sample-specific validity or reliability.
Conclusions: Despite efforts to implement MBIs in PwD, information on basic methodological psychometric issues is minimal. Future studies ought to address the validity and reliability of self-reported mindfulness in detail across different stages of dementia.
Clinical implications: Results of MBIs need to be considered cautiously. Basic information about psychometric properties of mindfulness self-report measures is required and these measures need to be included systematically in MBIs.
Epigenetic modifications play a pivotal role in the regulation of gene expression and cell function, offering potential markers of disease states and therapeutic outcomes. Recent advancements in neuroscience have spurred interest in studying the epigenetic underpinnings of psychosomatic medicine. This review presents a new perspective on the role of epigenetic regulation in the realms of psychosomatics and psychotherapy. The authors first highlight epigenetic patterns associated with prevalent psychosomatic disorders, including irritable bowel syndrome, fibromyalgia, psoriasis, and lichen planus. For these conditions, psychotherapy serves as a treatment modality and can be conceptualized as an epigenetic intervention that beneficially affects the epigenome as part of the therapeutic process. Focusing on cognitive-behavioral and mindfulness-based therapies, the authors highlight evidence on psychotherapy-associated epigenetic signatures occurring at genes that are involved in stress response, inflammation, neurotransmission, neuroplasticity, and aging. Educating patients about the potential of psychotherapy to affect the epigenome may enhance patient engagement with and adherence to treatment, and psychotherapy-induced epigenetic changes have the potential to promote transgenerational disease prevention, underscoring the far-reaching implications of this therapeutic approach. Challenges persist in epigenetic studies, and this review aimed to catalyze further research in this burgeoning field, with the goal of enhancing patient care.
RiSE study aims to evaluate a race-based stress-reduction intervention as an effective strategy to improve coping and decrease stress-related symptoms, inflammatory burden, and modify DNA methylation of stress response-related genes in older AA women. This article will describe genomic analytic methods to be utilized in this longitudinal, randomized clinical trial of older adult AA women in Chicago and NYC that examines the effect of the RiSE intervention on DNAm pre- and post-intervention, and its overall influence on inflammatory burden. Salivary DNAm will be measured at baseline and 6 months following the intervention, using the Oragene-DNA kit. Measures of perceived stress, depressive symptoms, fatigue, sleep, inflammatory burden, and coping strategies will be assessed at 4 time points including at baseline, 4 weeks, 8 weeks, and 6 months. Genomic data analysis will include the use of pre-processed and quality-controlled methylation data expressed as beta (β) values. Association analyses will be performed to detect differentially methylated sites on the targeted candidate genes between the intervention and non-intervention groups using the Δβ (changes in methylation) with adjustment for age, health behaviors, early life adversity, hybridization batch, and top principal components of the probes as covariates. To account for multiple testing, we will use FDR adjustment with a corrected p-value of <0.05 regarded as statistically significant. To assess the relationship between inflammatory burden and Δβ among the study samples, we will repeat association analyses with the inclusion of individual inflammation protein measures. ANCOVA will be used because it is more statistically powerful to detect differences.
Background
Medical students have high levels of stress, which is associated with higher incidents of burnout, depression, and suicide compared to age-matched peers. Mindfulness practices have been shown to reduce stress among medical students.
Purpose
The purpose of this systematic review and meta-analysis was to examine if mindfulness interventions have an overall effect on stress outcomes in the high-stress population of medical students globally, particularly given the wide variety of interventions. Any intervention designed to promote mindfulness was included.
Methods
A comprehensive literature search was completed to include multiple databases, ancestry, and hand-searching and 35 studies were included. Standardized mean difference effect sizes (ES) were synthesized across studies using a random-effects model for changes in stress levels in medical students ≥ 18. Moderator analyses were performed to explore variations in effects by participant and intervention characteristics.
Results
Mindfulness interventions significantly improved stress among medical students in both the two-arm studies (d = 0.370, k = 19, n = 2,199, 95% CI 0.239–0.501, p < .001) and one-arm pre-post studies (d = 0.291, k = 30, n = 18 (two cohorts from Dyrbye et al), 95% CI 0.127–0.455, p = 0.001). Moderator analyses found trends in less hours and less required practice resulted in better improvement in stress.
Conclusions
This study further confirms that despite a wide variety of mindfulness interventions for medical students around the world, they produce an overall small-to-moderate effect on stress reduction. Future research looking at the most effective protocols for high-stress medical students would be beneficial.
Neurodegenerative diseases (ND) have received increasing attention due to their irreversibility, but there is still no means to completely cure ND in clinical practice. Mindfulness therapy (MT), including Qigong, Tai Chi, meditation, and yoga, etc., has become an effective complementary treatment modality in solving clinical and subclinical problems due to its advantages of low side effects, less pain, and easy acceptance by patients. MT is primarily used to treat mental and emotional disorders. In recent years, evidence has shown that MT has a certain therapeutic effect on ND with a potential molecular basis. In this review, we summarize the pathogenesis and risk factors of Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), relating to telomerase activity, epigenetics, stress, and the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) mediated inflammatory response, and analyze the molecular mechanism basis of MT to prevent and treat ND, to provide possible explanations for the potential of MT treatments for ND.
Dysregulations of the hypothalamic-pituitary-adrenal (HPA) and sympatho-adrenal medullary (SAM) axis are associated with mental and somatic illness. However, there is lack of knowledge regarding the molecular mechanisms underlying these effects. Epigenetic states in the serotonin transporter gene (SLC6A4) were shown to be associated with stress in various forms. We hypothesized that levels of DNA methylation (DNAm) of SLC6A4 would be associated with altered SAM- and HPA regulation in daily life. N = 74 healthy persons participated in the study. An ecological momentary assessment (EMA) approach was used to assess indicators of stress in daily life. Each day included six concurrent assessments of saliva, to quantify cortisol (sCort; HPA axis) and alpha-amylase (sAA; SAM axis), and to assess self-reports on subjective stress. To assess SLC6A4 DNAm, peripheral blood was drawn and analyzed via bisulfite pyrosequencing. All data were assessed in two waves three months apart, each including two days of EMA and the assessment of SLC6A4 DNAm. Data were analyzed using multilevel models. On the between-person level, higher average levels of SLC6A4 DNAm were associated with higher average levels of sAA, but not with average levels of sCort. On the within-person level, higher levels of SLC6A4 DNAm were associated with lower levels of sAA and sCort. There were no associations of subjective stress with SLC6A4 DNAm. The results help to clarify the association between environmental stress and stress axes regulation, pointing towards an important role of differential within- and between-person effects of SLC6A4 DNAm, which might shape this association.
Oral ketamine has shown to be a rapid-acting antidepressant and a potential treatment option for suicidality, however, repeated doses are often required. Objective markers of prolonged treatment response are needed to help individuals and clinicians make informed treatment decisions. This secondary analysis sought to identify objective electrophysiological predictors of both prolonged response and dose sensitivity to low-dose oral ketamine in people with chronic suicidality. Individuals with a Beck Scale for Suicide Ideation total score (BSS) ≥ 6 (N = 29) completed a six-week ketamine treatment, pre-treatment electroencephalography and follow-up assessment of suicidality (four weeks from the final ketamine dose). Prolonged response was observed in 52% of participants (follow-up BSS reduced by 50% or ≤6); nearly half were prolonged non-responders. There was decisive evidence for a predictive Bayesian linear regression model with follow-up BSS score as the response variable and pre-treatment auditory evoked power bands as predictors (theta, alpha and beta frequencies, BF10 = 17,948, R2 = 0.70). A Bayesian one-way ANOVA indicated strong evidence for a model of positive association between auditory evoked power and ketamine dose sensitivity (theta-alpha BF+0 = 108, effect size δ = 1.3, 95% CI 0.5-2.1; high-beta BF+0 = 7.4, δ = 0.8, 95% CI 0.1-1.6). Given auditory evoked power may index serotonin neurotransmission, these results suggest that a prolonged response to ketamine may, in part, be mediated by pre-treatment serotonergic functioning. In addition, the observed beta power differences may arise from GABAergic functioning. These suicidality phenotypes, identifiable by pre-treatment electrophysiology, may aid diagnosis, treatment selection and prediction of prolonged treatment outcome.
Biomarkers of PTSD are greatly needed because of the challenges to diagnose and treat due to stigma, biases in self-reporting, and limitations of identifying those at risk and the scarcity of tools to predict treatment outcome. PTSD is influenced by both genetic and environmental factors as well as its interplay. Because of the dynamic and context-dependent nature of epigenetic modifications, these offer great promise as biomarkers of PTSD for the prevention, prognosis, and prediction of treatment outcome. In this chapter, genomic and epigenomic studies of PTSD are discussed. Epigenomic studies of PTSD conducted to date include DNA methylation (including DNA methylation age), histone modifications, and noncoding RNAs. Further, we discuss recent work using integrative multiomics approach as well as related gaps, challenges, and future directions aimed at identifying biomarkers of PTSD.
Research in genetics can not fully explain causality or the major contribution to stress-related psychiatric disorders such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). Epigenetic alterations are proven to have a crucial role between genetics and environmental effects. Epigenetic mechanisms, unlike genetic factors, are substantially dynamic and alterable, taking into account that they do not cause any change on the genetic material itself, rather, they change the expressions of genes. Thus the field of epigenetics also paves way for a therapeutic potential through mediating gene expression and regulating gene functions. The current chapter focuses on the role of epigenetic alterations in the etiology of these stress-related disorders. Yet, while the reported associations between epigenetics and stress-related disorders are not strong enough to predict a causal relationship, and research on epigenetics is relatively incipient, further studies are clearly needed.
Early life adversities (ELA) are prevalent and have a profound and adverse impact across the lifespan, including on age-related health outcomes, yet interventions to remediate its adverse impact are scarce. This paper presents evidence for mindfulness training to reduce the elevated mental and physical health risks linked to ELA among adults by targeting biological mechanisms of ELA leading to these adverse health outcomes. We first provide a brief overview of ELA, its adverse health impacts, and mechanisms that might be responsible. Next, we review converging evidence that demonstrates that mindfulness training influences key biological pathways involved in ELA-linked negative health consequences, including (a) brain networks involved in self-regulation, (b) immunity and inflammation, (c) telomere biology, and (d) epigenetic modifications. Further, we review preliminary evidence from mindfulness-based trials that focused on populations impacted by ELA. We discuss limitations of this review and provide recommendations for future research. If effective, a mindfulness-based approach could be an important public health strategy for remediating the adverse mental and physical health consequences of ELA.
Accumulating evidence supports epigenetic processes as important determinants of individual susceptibility or resilience to the development of psychiatric disorders. Like every intervention that promotes resilience, psychotherapy necessitates changes in neurocircuitry and neurotransmission, and such changes are in turn associated with underlying lasting changes in cell and genomic function. Consequently, psychotherapy can be hypothesized to promote an epigenetic fingerprint that is conducive to stress resilience. To date, a small number of studies – including either an epigenome-wide approach or a hypothesis-driven examination of genes that regulate the stress response, neural plasticity, or neurotransmission – have addressed the potential relevance of peripheral blood DNA methylation changes in response to psychotherapy. The findings to date suggest that psychotherapy-related symptom reductions are associated with concomitant epigenetic changes in peripheral blood. However, future studies will need to address the potential of epigenetic modifications to serve as biomarkers for psychotherapeutic interventions.
Stress is associated with mental health problems and physical diseases. Results from basic research indicate that stress-induced dysregulations of bodily stress response systems might mediate these processes. In consequence, many programs to prevent or manage stress have been developed and evaluated using endpoints of these bodily stress systems. Over the last few years, emerging evidence from human and animal studies has indicated that stress also leads to changes in epigenetic signatures. The functional consequences of these changes, among them altered gene expression, have been shown to modulate the psychobiological stress response. Some recent studies now show that psychosocial interventions, such as stress prevention and stress management, can alter epigenetic processes. In this review, we will present an outline on (1) relevant epigenetic mechanisms, (2) the current literature on the association of stress and epigenetics, and (3) mechanisms through which psychological interventions might alter stress-related epigenetic markers.
Chronischer oder traumatischer Stress kann psychische Störungen und körperliche Erkrankungen begünstigen oder sogar verursachen. Ergebnisse aus der Grundlagenforschung zeigen, dass Stress zu einer Dysregulation wichtiger körperlicher Stresssysteme führen kann, welche diese Prozesse vermutlich vermitteln. Hierauf aufbauend wurden Interventionen zur Prävention oder zum Umgang mit Stress entwickelt, deren Wirkung mittels verschiedener Indikatoren dieser Stresssysteme evaluiert werden kann. In den letzten Jahren zeigten Ergebnisse aus Tier- und Humanstudien, dass sich Stress auch auf epigenetische Signaturen auswirken kann. Die funktionellen Konsequenzen dieser Veränderungen, darunter eine veränderte Expression der betroffenen Gene, wurden zudem als Modulatoren der psychobiologischen Stressantwort beschrieben. Eine Reihe erster Pionierstudien zeigt nun, dass stressassoziierte epigenetische Prozesse durch psychologische Interventionen, darunter Stressprävention und Stressbewältigung, verhindert oder sogar umgekehrt werden können. In der vorliegenden Übersichtsarbeit werden (1) relevante epigenetische Mechanismen beschrieben, (2) eine Übersicht zum Zusammenhang von Epigenetik und Stress dargestellt und (3) erläutert, wie epigenetische Prozesse durch psychologische Interventionen beeinflusst werden könnten.
Mindfulness Based Stress Reduction (MBSR) is an effective non-pharmacologic treatment for veterans with PTSD. Extensive work has identified epigenetic factors related to PTSD disease risk and pathophysiology, but how these factors influence treatment response is unclear. Serotonin signaling and hypothalamic-pituitary-adrenal (HPA) axis functioning may be perturbed in PTSD and are molecular pathways targeted by PTSD treatments. To identify potential biomarkers for treatment response, we utilized genomic DNA isolated from peripheral blood samples from veterans with PTSD who were responders (n = 11) or non-responders (n = 11) to MBSR as part of a clinical trial. We assessed methylation levels at CpG sites in regions of the serotonin transporter (SLC6A4) previously associated with expression and depression outcomes, as well as the Intron 7 region of the FK506 binding protein 5 (FKBP5) containing known glucocorticoid response elements suggested to regulate this gene. Selected subjects were matched across MBSR responder status by baseline symptoms, age, sex, current smoking status, and current antidepressant use. Percent methylation was compared between responders and non-responders at baseline (pre-MBSR treatment). Additionally, percent change in methylation from baseline to post-treatment was compared between responders and non-responders. There was a significant time x responder group interaction for methylation in FKBP5 intron 7 bin 2 [F(1, 19) = 7.492, p = 0.013] whereby responders had a decrease in methylation and non-responders had an increase in methylation from before to after treatment in this region. Analyses of the three CpG sites within bin 2 revealed a significant time x responder group interaction for CpG_35558513 [F(1, 19) = 5.551, p = 0.029] which resides in a known glucocorticoid response element (GRE). Decreases in FKBP5 methylation after treatment in responders as compared to increases in non-responders suggest that effective meditation intervention may be associated with stress-related pathways at the molecular level. These preliminary findings suggest that DNA methylation signatures within FKBP5 are potential indicators of response to meditation treatment in PTSD and require validation in larger cohorts.
Meditation can be defined as a form of mental training that aims to improve an individual's core psychological capacities, such as attentional and emotional self-regulation. Meditation encompasses a family of complex practices that include mindfulness meditation, mantra meditation, yoga, tai chi and chi gong 1. Of these practices , mindfulness meditation — often described as non-judgemental attention to present-moment experiences (BOX 1) — has received most attention in neuroscience research over the past two decades 2–8. Although meditation research is in its infancy, a number of studies have investigated changes in brain activation (at rest and during specific tasks) that are associated with the practice of, or that follow, training in mindfulness meditation. These studies have reported changes in multiple aspects of mental function in beginner and advanced meditators, healthy individuals and patient populations 9–14. In this Review, we consider the current state of research on mindfulness meditation. We discuss the methodological challenges that the field faces and point to several shortcomings in existing studies. Taking into account some important theoretical considerations, we then discuss behavioural and neuroscientific findings in light of what we think are the core components of meditation practice: attention control, emotion regulation and self-awareness (BOX 1). Within this framework, we describe research that has revealed changes in behaviour, brain activity and brain structure following mindfulness meditation training. We discuss what has been learned so far from this research and suggest new research strategies for the field. We focus here on mindfulness meditation practices and have excluded studies on other types of meditation. However, it is important to note that other styles of meditation may operate via distinct neural mechanisms
Current diagnostic definitions of psychiatric disorders based on collections of symptoms encompass very heterogeneous populations and are thus likely to yield spurious results when exploring biological correlates of mental disturbances. It has been suggested that large studies of biomarkers across diagnostic entities may yield improved clinical information. Such a view is based on the concept of assessment as a collection of symptoms devoid of any clinical judgment and interpretation. Yet, important advances have been made in recent years in clinimetrics, the science of clinical judgment. The current clinical taxonomy in psychiatry, which emphasizes reliability at the cost of clinical validity, does not include effects of comorbid conditions, timing of phenomena, rate of progression of an illness, responses to previous treatments, and other clinical distinctions that demarcate major prognostic and therapeutic differences among patients who otherwise seem to be deceptively similar since they share the same psychiatric diagnosis. Clinimetrics may provide the missing link between clinical states and biomarkers in psychiatry, building pathophysiological bridges from clinical manifestations to their neurobiological counterparts. © 2014 S. Karger AG, Basel.
The serotonin reuptake transporter (5HTT) is thought to be the principal regulator of serotonergic activity and epigenetic effects at this locus are thought to be important moderators of vulnerability to neuropsychiatric illness. In attempt to understand the basis of this regulation, several gene polymorphisms that affect 5HTT mRNA levels have been described. But to date, no clear mechanism linking these polymorphisms to vulnerability to epigenetic effects have been described. In this communication, we describe a CpG island in the 5' region of the 5HTT gene that contains an alternative exon 1 and possible promoter for 5HTT. We then confirm the existence of this transcript and ascertain the methylation status of this CpG island in 49 lymphoblast cell lines and analyze the relationship between methylation and 5HTT mRNA levels. We demonstrate that methylation at this CpG island is associated with decreased levels of 5HTT mRNA, but that this effect is evident only when 5HTTLPR genotype is taken into account. We suggest that these findings have significant implications for the understanding of the role of this locus in behavioral illness.
The gene encoding the serotonin transporter (5-HTT) contains a regulatory variation that has been associated with anxiety-related traits and susceptibility for depression. Here we highlight recent discoveries related to allelic variation of 5-HTT function with respect to emotion regulation and social behavior, drawing from an interdisciplinary perspective of behavioral genetics and cognitive neuroscience. Following a reductionistic path that leads from gene-behavior association studies to neuroimaging and epigenetic studies, we compare two models of 5-HTT-dependent modulation of brain activity and discuss the role of life stress experience in modifying 5-HTT function in the brain. Integration of these findings suggests that the impact of the 5-HTT gene on behavior is much broader than is commonly appreciated and may have a role in social cognition.
Two different methods of presenting quantitative gene expression exist: absolute and relative quantification. Absolute quantification calculates the copy number of the gene usually by relating the PCR signal to a standard curve. Relative gene expression presents the data of the gene of interest relative to some calibrator or internal control gene. A widely used method to present relative gene expression is the comparative C(T) method also referred to as the 2 (-DeltaDeltaC(T)) method. This protocol provides an overview of the comparative C(T) method for quantitative gene expression studies. Also presented here are various examples to present quantitative gene expression data using this method.
Gene—environment (GxE) interactions have largely been regarded as the root of many complex disorders, including several psychiatric disorders. In this regard, it has been hypothesized that epigenetic mechanisms may be the main mediators of such interactions. Of particular interest is the previously described interaction between psychosocial stress and genetic variability of the serotonin transporter gene (SLC6A4) in its polymorphic region 5-HTTLPR. Here we review the literature concerning SLC6A4 methylation in association with environmental, clinical or genetic variables. While SLC6A4 hypermethylation has typically been described to be independently associated with both early life stress and depressive disorders, only a few papers address whether methylation could mediate the interaction between stress and 5-HTTLPR in predicting psychopathological risk. Nevertheless, research preliminarily indicates a methylation-driven increased vulnerability of carriers of the short allele of 5-HTTLPR to psychiatric disorders when exposed to early stress or soon after exposure to stress.
The application of epigenetics to the study of behavioral and socio-emotional development in humans has revealed that DNA methylation could be a potential marker of adversity exposure and long-lasting programming of health and disease. The serotonin transporter gene (SLC6A4) is a stress-related gene which has well-documented implications for behavioral and socio-emotional development and which has been shown to be susceptible to transcriptional regulation via epigenetic mechanisms. In the present paper, a systematic review of papers assessing the association among adversity exposures, SLC6A4 methylation and developmental outcomes is reported. Nineteen studies were included. Findings revealed that SLC6A4 methylation has been investigated in humans in association with a number of prenatal and postnatal adverse exposures, encompassing maternal depression during pregnancy, perinatal stress exposure, childhood trauma and abuse, and environmental stress. SLC6A4 is confirmed as a relevant biomarker of early adversity exposures, and epigenetic mechanisms occurring at this gene appear to play a critical role for programming. Nonetheless, specific methodological issues still need to be addressed in future human behavioral epigenetic research.
... Thomas D Schmittgen 1 & Kenneth J Livak 2 . ABSTRACT. ... N. Engl. J . Med. ... 32, e178 (2004). | Article | PubMed | ChemPort |; Livak , KJ & Schmittgen , TD Analysis of relative gene expression data using real - time quantitative PCR and the 2 (- Delta Delta C(T)) Method . ...
Zusammenfassung: Eine empirische Beforschung des Achtsamkeitskonzepts erfordert auch die Erfassung des Konstruktes selbst. Ob dies prinzipiell mit dem gegebenen metho- dischen Inventar der Psychologie möglich ist, wird kurz diskutiert. Zwei bereits im eng- lischen Sprachraum existierende Instrumente werden skizziert, bevor die Konstruktion und Validierung des Freiburger Fragebogens zur Achtsamkeit (FFA) beschrieben wird. Zunächst wurde auf der Basis einer Literaturstudie und anschließender Bewertung durch ExpertInnen ein Fragebogen mit 38 Items erarbeitet. Dieser wurde an Stichproben von 115 TeilnehmerInnen an einem Vipassana-Retreat jeweils vor und nach dem Retreat aus- gefüllt. Aus diesen Daten konnte die 30-Item-Langform des FFA gebildet werden, die mit
Empirische Erfassung der Achtsamkeit – Die Konstruktion des Freiburger Fragebogens zur Achtsamkeit (FFA) und weitere Validierungsstudien; in Heidenreich T, Michalak J (eds): Achtsamkeit und Akzeptanz in der Psychotherapie. Ein Handbuch. Tübingen, dgvt-Verlag, , pp 729-772.
- H Walach
- N Buchheld
- V Buttenmüller
- N Kleinknecht
- P Grossmann
- S Schmidt