Editorial I

The Physiological Basis of Mind-Body Medicine

by Maja Figura¹ and Tobias Esch²

Mind-body medicine (MBM) is a modern form of stress medicine (Esch & Stefano, 2010; Esch & Stefano, 2022). It was developed by the American cardiologist and professor of medicine at Harvard Medical School, Herbert Benson (M.D.). As a counterpart to Walter B. Cannon's discovery of the body’s “fight or flight” response  (Cannon, 1915), Benson coined the term relaxation response (RR), a physiological response reaction of the body to stress (Cannon, 1915). Techniques that elicit a RR are the basis of virtually all MBM interventions (MBI) (Esch et al., 2018). Together with Integrative Medicine, MBM forms Complementary and Integrative Health (Esch & Brinkhaus, 2020). According to the approach of salutogenesis, the self-healing potential is used to build up and facilitate individual resources (Esch, 2020). Thus, MBM offers the opportunity to make an important contribution to individual health care by helping people to help themselves (Dineen-Griffin et al., 2019).
Based on the idea that thoughts and emotions have an impact on health, MBM effects manifest, e.g., at the psychoneuroimmunological level (Magan & Yadav, 2022). Psychoneuroimmunology is an interdisciplinary field of research that focuses on the role of neuro-immune interactions in coping with stressors (Ader, 2007; Godoy et al., 2018). Stress results from an interplay of biological and adaptive processes (Godoy et al., 2020). These processes involve a variety of different brain areas that can interpret events as real or potential threats. This is followed by a rapid activation of the autonomic nervous system via the sympathetic-adreno-medullary (SAM) axis and the hypothalamic-pituitary-adrenal (HPA) axis (Figure 1) (Stefano et al., 2005).

Figure 1. The stress response simplification based on Godoy et al. (2018).

SAM = sympathetic-adreno-medullary axis, 

HPA = hypothalamic-pituitary-adrenal axis

In addition to the classical stress mediators cortisol and (nor-) adrenaline, a wide range of neuroendocrine signaling molecules areinvolved. These lead to an adaptation of the cardiovascular system such as increased heart rate, blood pressure and immune response. Short-term stress seems to increase the ability to perform. Problems arise when permanent and/or excessive stress occurs (Chrousos & Gold, 1992; Esch et al., 2002; Esch & Stefano, 2010). Chronic stress can lead to suppression of protective immune responses and exacerbation of pathological immune responses (Dhabhar, 2014).

Editorial II

A Brief Account of the Very Early History of Pandemics

by George B. Stefano^1,2

The history of infectious disease outbreaks and plagues among human populations is long, as recorded in centuries-old religious and secular texts, as well as through Indigenous oral histories (Edinborough et al., 2017; Huremović, 2019; Stefano, 2021). One early account is of a plague that ravaged parts of North Africa and Greece in the late 5th century BCE. Known as the Athenian Plague, it was detailed at the time by the Greek historian, Thucydides, in his History of the Peloponnesian War. Over the course of a week or more, a series of gruesome symptoms would travel from head to toe – from “inflammation of the eyes”, bloody throat, violent retching, breakouts of “pustules and ulcers”, and diarrhea, among others. For those who recovered, a reported loss of memory left them not knowing “themselves or their friends” (Thucydides, 2003). Greatly devastating the population of Athens, it has been recently suggested that it may have been an ancient outbreak of the Ebola virus (Chastel, 1996).

Research

The BERN Framework of Mind-Body Medicine

by Tobias Esch¹ and George B. Stefano^1,2

In the University Outpatient Clinic for Integrative Health Care and Naturopathy at Witten/Herdecke University, which emerged from the Institute for Integrative Health Care and Health Promotion (IGVF), the so-called BERN program has been taught to patients since 2019.

The BERN concept, a health promotion program is based on the concept of Mind-Body Medicine (MBM), which was developed at Harvard Medical School in Boston. MBM focuses on enhancing our understanding of how the interactions between the brain, mind, body, and behavior can be utilized to improve health and well-being (Esch, 2020).

The evidence base of the BERN program has recently been published by Tobias Esch and George Stefano in an article in Frontiers in Integrative Neuroscience (Esch & Stefano, 2022).

In this narrative review, the fundamental principles of MBM are outlined and a logical framework for implementing interventions based on MBM are introduced. Additionally, the impact of MBM on the brain’s motivation and reward systems is explored, including potential involvement of mitochondria.

MBM can effectively enhance the health of individuals with chronic diseases, particularly those linked to lifestyle factors. It builds upon the concept of salutogenesis, which concentrates on determinants of health rather than disease and emphasizes the development of individual

The Integration of AI in Mental Health Assessment: Leveraging Digital Biomarkers and Behavioral Data

by Maren M. Michaelsen¹ and and Tobias Esch¹

Current psychiatric assessment methods are resource-intensive, requiring time-consuming evaluations by trained clinicians. AI offers the potential for scalable and cost-effective assessment of psychiatric diagnosis and symptom change (Barnett et al., 2018; Ćosić et al., 2021; Jacobson et al., 2019b; Pedrelli et al., 2020). AI algorithms can analyze large datasets collected from various sources, such as wearable devices, smartphones, and online platforms, to identify patterns and extract relevant features. This enables the identification of digital biomarkers associated with mental health conditions. AI techniques, such as machine learning and deep learning, can build predictive models based on these identified digital biomarkers, process complex data and detect subtle changes in behavior or physiological signals that may indicate symptom severity or predict relapse. Based on this, AI-powered technologies enable remote monitoring of individuals’ mental health. This can reduce the burden on patients and clinicians, as well as enhance accessibility to mental health care, e.g., by providing real-time insights and alerts to healthcare providers about changes in symptom severity or potential relapse. In addition, AI can support the development of personalized interventions by analyzing individual data and providing tailored recommendations or interventions based on an individual’s specific needs. For example, AI algorithms can identify behavioral anomalies or changes in real-time smartphone data and, as a consequence, trigger timely interventions, such as providing reminders, coping strategies, or connecting individuals with mental health support services. Finally, AI can assist clinicians in making more informed decisions by providing them with additional information and insights.

The field of research exploring digital movement patterns as potential biomarkers for mental diseases, such as depression and schizophrenia, as well as examining online shopping behaviors and environmental radius/GPS data, is rapidly growing (e.g., Jacobson et al., 2020; Jacobson et al., 2019a; Saeb et al., 2015). Research has explored the use of smartphone sensor data, such as GPS and usage sensors, as well as social contact data, in monitoring behavioral patterns indicative of depressive symptoms (Jacobson et al., 2019b; Pedrelli et al., 2020; Saeb et al., 2015). One study investigated the use of passive movement and light data collected from wearable devices to assess depression severity in patients with major depressive disorder (Jacobson et al., 2019b). By analyzing over a week of movement data, the researchers were able to significantly evaluate depression severity with high precision, both for self-reported and clinician-rated symptom severity. Another study re-analyzed public-use actigraphy data from patients with major depressive

Antibiotics and Antiviral Agents Can Trigger Mitochondrial Dysfunction that Leads to Psychiatric Disorders

by George B. Stefano^1,2

Antibiotics and antiviral agents represent a diverse array of chemical agents that can be used to prevent and treat acute and chronic bacterial and viral infections. Unfortunately, many of these drugs have become less effective because these pathogens have developed a variety of resistance mechanisms. This requires us to develop new and different drugs that target unique aspects of bacterial and viral invasion and replication processes. By doing so, we may inadvertently create new drugs that influence other endogenous processes, including human behavior. This is because the structures of some of these new drugs may share critical shape features with naturally-occurring endogenous biochemicals and thus may interfere with their critical functions in vivo.

Discussion

Many antibacterial agents are inherently toxic to the host. This may be due at least in part to the unique evolutionary relationships that link molecular mechanisms of mammalian mitochondria to primordial processes that developed originally in their bacterial progenitors. Mitochondria, which are cellular organelles that generate ATP in the mammalian host cell, are the descendants of enslaved bacteria. Mitochondrial ribosomal (r)RNA in healthy cells is a critical target for new drug development. Mitochondrial rRNA has a similar structure and function to that found in bacteria and incorporates mutations more rapidly than mammalian nuclear rRNA. Given its propensity to incorporate mutations, the mitochondrial rRNA and mitochondria themselves become prone to dysfunction. Antibiotics designed to target pathogens may also exhibit high-affinity interactions with mammalian mitochondria that result in adverse effects. Minocycline is an example of a drug that promotes ATP synthesis and calcium retention in brain cell mitochondria that may have a direct impact on one or more psychiatric disorders. Antimicrobial-induced mania, or antibiomania, is a term used to address changes in mental health status that result directly from the administration of antibiotic agents.

With this in mind, we and others have proposed that mitochondrial dysfunction may be among the core issues leading to psychiatric dysfunction induced by antibiotic treatment, including depression and autism. Antibiotic-induced dysfunctional mitochondria have recently emerged as one of the root causes of several psychiatric disorders. For example, a small percentage of patients treated with ciprofloxacin ultimately develop psychosis. Behavioral changes have also been observed in response to metronidazole, ofloxacin, procaine penicillin, and clarithromycin. These findings suggest that translation-targeting antibiotics should be used with extreme caution, especially in patients diagnosed with mitochondrial translation defects. The long-term effects of antibiotics on mitochondrial function and integrity have yet to be determined.

Although eukaryotic cells can recognize bacteria and respond with rudimentary host defense, the bacterium typically has the advantage. The prokaryotic bacterial organism has been evolving for millions of years and is capable of subverting the innate immune response. This capacity may in part be based on conserved common molecular mechanisms and intracellular components.

NEW: Student’s corner

PhD Project: Digital Mindfulness Interventions in Oncology Work Environments

by Jil Herker¹

Background

Medical technologists in radiology (MTR) are exposed to high work demands. In an international double-blind study (Beschoner et al., 2022), 97% of German MTRs and employees in imaging technology reported experiencing moderate to severe stress. As a cause, 95% of respondents mentioned the level of workload. The shortage of specialists, as evidenced by the immediate need for 840 MTR positions nationwide, feeds into the stress factor workload. This shortage is unlikely to be alleviated in the near future since 25% of currently practicing MTRs will retire by 2030 for age reasons (Blum, 2019). Specifically, staff shortages, overtime, and direct contact with Covid-19 infected individuals/materials are considered as drivers of work stress for MTRs during the pandemic. Investigations and improvements of the stress experience are essential to conquer this potential health hazard (Koninklijke Philips, 2019).

MTRs in radiotherapy encounter numerous cancer patients every day to perform radiotherapy with them. This not only entails a high level of coordination and the resulting organizational stress. The emotional stress of the cancer patients also presents a challenge to the mental health of the MTRs. The skills of stress and emotion regulation as well as self-care are therefore important resources for MTRs to cope with everyday work and to stay healthy.

Research aim and method

The study “Mindfulness Interventions in Oncology Work Environments” is designed, first, to determine whether digital health promotion interventions are effective in reducing the experience of stress in MTRs. On the other hand, two apps – a digital, modern meditation intervention (7Mind app) and a digital, traditional breathing exercise intervention (Pranayama app) – will be used to explore effects on stress experience and health promotion, among other outcomes, in MTRs to draw conclusions on the feasibility and effectiveness of the components.

Prior to the intervention, all MTRs are made aware of the relevance of self-care in an approximately half-hour awareness-raising intervention during working hours, e.g. as part of an internal meeting. The intervention is offered twice per facility in order to ensure that work operations are maintained. Since no person-level randomization can take place due to structural conditions, the MTRs will be assigned to the intervention groups (7Mind app or Pranayama app) according to quasi-experimental

Editorial

Personalized and One Medicine Coming Together

by George B. Stefano^1,2

In an earlier publication (see for detailed information and references [1]), we highlighted the contributions of new genetic and bioinformatics tools to the development of personalized medicine. We also considered how these developments might be used to accelerate advances and reduce healthcare costs based on the principles of One Medicine.

Personalized medicine focuses on the development and application of therapeutic strategies that are tailored to specific patient characteristics. One successful example of this direction is trastuzumab, which is a humanized monoclonal antibody used to treat patients diagnosed with advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Similarly, cetuximab and panitumumab are monoclonal antibody drugs that have been approved by the United States Food and Drug Administration as targeted treatment of epidermal growth factor-(EGFR) positive metastatic colon cancers.

While the introduction of these and related drugs has created a virtual revolution in clinical care, future development of personalized therapies will depend on increased knowledge and understanding of the unique features of each patient and each disease. Ongoing advances will rely on comparatively new and highly sophisticated methods used to explore genome sequences and gene expression both in health and disease states. Among these is whole genome sequencing (WGS), which is a process used to elucidate the sequence and chromosomal localization of the ~3 billion nucleotide pairs in the human genome. While the first near-complete human genome sequence was reported in 2004, several more recent methodologic advances, including whole exome sequencing and single nucleotide polymorphism (SNP) genotyping, have served to advance the field and accelerate discovery. As a group, these tools can be used to identify genetic variation (e.g., polymorphisms and potentially-damaging mutations) and thus may aid in the diagnosis and discovery of genetic diseases and their associated risks. These tools were originally quite time-consuming and prohibitively expensive to perform which precluded their use in routine clinical practice. However, in recent years, some inroads have been made toward using genomic information collected by these methods to develop personalized strategies that address the needs and concerns of physicians and patients.

While WGS and related techniques can provide information on gene structure and sequence, in some cases it may be more critical to evaluate patterns of gene expression. For example, cancers are now frequently classified based on their gene expression patterns rather than their location or tissue of origin. Microarray and RNA sequencing (RNAseq) are two techniques that have been used to evaluate gene expression in specific target cells and tissues. Microarray analysis relies on the quantitative evaluation and interpretation of binding interactions between cellular RNA isolated from target cells of interest and short fragments of nucleic acid sequences (probes) affixed to a surface. This technique has broad application beyond gene expression and is already in clinical use as a means to diagnose viral infections via unbiased detection of viral DNA or RNA genomes. By contrast, RNAseq is a more open-ended and flexible method for evaluating gene expression, as it can be used for simultaneous identification of both characterized and as yet uncharacterized transcripts from multiple sources (e.g., the numerous 

Research

Mobility Coupled with Motivation Promotes Survival: The Evolution of Cognition as an Adaptive Strategy

by George B. Stefano^1,2, Richard M. Kream² and Tobias Esch¹

In a recent publication [1], we present the hypothesis of an evolutionary and functional relationship between the occurrence and use of the catecholamine dopamine (DA) as a neurotransmitter (messenger)—particularly in invertebrates—and the catecholamines epinephrine (EP) and norepinephrine (NE), messengers that are found only in vertebrates. Interestingly, both are also involved in pathways leading to the production of endogenous morphine, another messenger substance. We assume that the use of EP/NE as messengers represents an evolutionary advantage and adaptation process, whereby this “metabolite” (its biochemical intermediates) is only used “in retrospect” as a neurotransmitter (evolutionary “retrofitting”); on the way to greater 

Research

Personalized Medicine and Personalized Health Promotion Based on Motivation and Reward Proceedings
by Maren M. Michaelsen¹

As the number of patients with lifestyle-related chronic diseases continues to increase worldwide [1], the need for personalized medicine is growing. At the same time, the development and implementation of prevention and health promotion interventions to help individuals change their health behaviors is becoming increasingly important. While personalized medicine focuses on the development and application of therapeutic strategies tailored to specific patient characteristics, such as specific antibodies, personalized health promotion focuses on specific patient lifestyle characteristics, such as diet, exercise and relaxation behaviors (or stress management). Thus, supporting patients change specific negative health behaviors that they perform on a regular basis is the focus of contemporary health promotion. Examples of tools with this objective include technological applications such as fitness trackers that connect to mobile phone apps and suggest behaviors based on the measurement (e.g., walking more steps the next day). However, these technological advances are often available to clients before their effectiveness has been examined in research studies. In addition, the development of health behavior change techniques often occurs without an adequate theoretical basis about the psychological or neurobiological processes involved in health behavior change. This imposes the risk of decreasing patient engagement over time because extrinsic motivational incentives are not strong enough to build sustained engagement. 

To better understand patients’ engagement in health behavior change processes, in [2], we have analyzed the role of motivation and reward proceedings at different stages of behavior change processes. Our analysis is based on the triad of motivation and reward mechanisms, which include approach motivation (wanting) with its associated reward pleasure, aversive motivation (avoiding) with its associated reward relief, and assertion motivation (non-wanting) with its  

By applying motivational interviewing or other tools, it is possible to determine which stage of a particular health behavior change process an individual currently is at and what is needed to progress to another stage. For example, imagine a person who regularly watches Netflix series for relaxation in the evening and has just learned that breath awareness meditation leads to a physiologically better relaxation response. This person has just moved from the unawareness stage to the awareness stage. To progress to the contemplation stage, motivational cues are needed that activate appetitive motivational salience and thereby make the new behavior more attractive. This motivational cue could be the information that by replacing one episode

Research

Combining App-based Behavioral Support with Electronic Nicotine Delivery System Devices for Smoking Cessation

by Cosima Hoetger¹, Helen Schiek¹

Worldwide, tobacco use causes over 7 million deaths annually [1]. As of 2022, over 35% of Germans report current use of cigarettes. Approximately 38% of current smokers report wanting to quit smoking [2]. However, about 80% of individuals who attempt to quit smoking without support relapse within a month; only 3% remain abstinent six month later [3]. Treatment methods outlined in medical guidelines are rarely used, and both the effectiveness of and adherence to these interventions remain low [4,5], necessitating the development of novel and effective smoking cessation methods. 

Electronic nicotine delivery systems (ENDS) have been found to be more effective in helping smokers quit than recommended cessation methods [6]. Their effectiveness can be further increased if coupled with a behavioral support component [7]. These findings highlight the need for smoking intervention efforts that target the physical as well as the psychological mechanisms of nicotine dependence. Recognizing the importance of holistic approaches to smoking cessation, the Berlin-based startup company Sanos Group developed an integrated smoking cessation intervention (‘nuumi’). The smoking cessation program is accessible via a smartphone app, thus allowing users to personalize their intervention experience by having control over the place and time they wish to interact with the app [8]. Additionally, digitalized interventions allow for further personalization of health-related information by tailoring content to users’ needs, e.g. via personalized text messages [9].

Nuumi offers an app-based behavioral support consisting of video and audio recordings and interactive exercises, coupled with a bluetooth-supported ENDS device. The behavioral support consists of the digitalized content of a health promotion course developed by Tobias Esch; the course framework is described elsewhere [10]. The digitalized course features content derived from four areas, including Behavior, Exercise, Relaxation, and Nutrition (BERN). In order to meet the specific needs of smokers motivated to quit, the course content has been tailored to help individuals overcome barriers frequently encountered during smoking cessation attempts. For example, smokers report greater stress levels relative to nonsmokers, and one of the most frequently reported reasons for continued smoking is the management of stress and negative emotions [11,12]. Stress and negative emotions can even increase during withdrawal [13], creating a barrier to successful smoking cessation [14]. App content and exercises draw from Mind-Body Medicine-based techniques designed to foster social, psychological, behavioral, and spiritual wellbeing [15] and decrease negative emotions 

The Mind-Body Medicine Research Council 

Exploring the Details of Body and Mind That Account for a Healthy Life in an Uncertain World
by Maren M. Michaelsen^1, George B. Stefano^1,2, Tobias Esch¹

Pandemic, war, climate change, artificial intelligence – Our world and our lives are full of challenges that require a high level of psychological resistance and coping. Since the mind and the body are interconnected, it is important to develop, implement, evaluate and understand measures at both levels for a healthy and thriving society.

The Mind-Body Medicine Research Council (MBMRC) aims to analyze these aspects in their details. The MBMRC is hosted by the Institute for Integrative Health Care and Health Promotion (IGVF), Faculty of Health/School of Medicine at Witten/Herdecke University, Germany. The institute focuses its attention on improving primary health care and increasing the effectiveness of health promotion efforts for patients. While the implications of our research findings certainly contribute to improving health outcomes at the population level, our focus remains on the individual and their personal resources as well as the pathways through which protective (salutogenetic) factors – including, but not limited to, resilience, self-efficacy, self-care and -healing, and the motivation to improve one’s personal health behaviors – can be activated and strengthened.

For this, we apply basic and applied sciences, from neurobiology to general health research, including integrative as well as Mind-Body Medicine (MBM). Tobias Esch, a university professor, researcher, and physician, serves as the institute’s director and has founded the university’s outpatient clinic in general medicine, thus