Hormesis and neural stem cells.

This paper provides a detailed identification and assessment of hormetic dose responses in neural stem cells (NSCs) as identified in a number of animal models and human tissues, with particular emphasis on cell proliferation and differentiation. Hormetic dose responses were commonly observed following administration of a number of agents, including dietary supplements [e.g., berberine, curcumin, (-)-epigallocatechin-3-gallate (EGCG), Ginkgo Biloba, resveratrol], pharmaceuticals (e.g., lithium, lovastatin, melatonin), endogenous ligands [e.g., hydrogen sulfide (H2S), magnesium, progesterone, taurine], environmental contaminants (e.g., arsenic, rotenone) and physical agents [e.g., hypoxia, ionizing radiation, electromagnetic radiation (EMF)]. These data indicate that numerous agents can induce hormetic dose responses to upregulate key functions of such as cell proliferation and differentiation in NSCs, and enhance resilience to inflammatory stresses. The paper assesses both putative mechanisms of hormetic responses in NSCs, and the potential therapeutic implications and application(s) of hormetic frameworks in clinical approaches to neurological injury and disease.

Hormesis and Ginkgo biloba (GB): Numerous biological effects of GB are mediated via hormesis.

Ginkgo biloba (GB) extracts have been shown to commonly induce biphasic dose responses in a range of cell types and endpoints (e.g., cochlea neural stem cells, cell viability, cell proliferation). The magnitude and width of the low dose stimulation of these biphasic dose responses are similar to those reported for hormetic dose responses. These hormetic dose responses occur within direct stimulatory responses as well as in preconditioning experimental protocols, displaying acquired resistance within an adaptive homeodynamic and temporal framework and repeated measurement protocols. The demonstrated GB dose responses further reflect the general occurrence of hormetic dose responses that consistently appear to be independent of the biological model, endpoint, inducing agent, and/or mechanism. These findings have important implications for consideration(s) of study designs involving dose selection, dose spacing, sample size, and statistical power. This illustrates and strengthens the need to characterize the low dose stimulatory response range and optimal dose in order to explore potential public health and clinical applications of plant-derived agents, such as GB.

Limited output transcranial electrical stimulation (LOTES-2017): Engineering principles, regulatory statutes, and industry standards for wellness, over-the-counter, or prescription devices with low risk.

We present device standards for low-power non-invasive electrical brain stimulation devices classified as limited output transcranial electrical stimulation (tES). Emerging applications of limited output tES to modulate brain function span techniques to stimulate brain or nerve structures, including transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial pulsed current stimulation (tPCS), have engendered discussion on how access to technology should be regulated. In regards to legal regulations and manufacturing standards for comparable technologies, a comprehensive framework already exists, including quality systems (QS), risk management, and (inter)national electrotechnical standards (IEC). In Part 1, relevant statutes are described for medical and wellness application. While agencies overseeing medical devices have broad jurisdiction, enforcement typically focuses on those devices with medical claims or posing significant risk. Consumer protections regarding responsible marketing and manufacture apply regardless. In Part 2 of this paper, we classify the electrical output performance of devices cleared by the United States Food and Drug Administration (FDA) including over-the-counter (OTC) and prescription electrostimulation devices, devices available for therapeutic or cosmetic purposes, and devices indicated for stimulation of the body or head. Examples include iontophoresis devices, powered muscle stimulators (PMS), cranial electrotherapy stimulation (CES), and transcutaneous electrical nerve stimulation (TENS) devices. Spanning over 13 FDA product codes, more than 1200 electrical stimulators have been cleared for marketing since 1977. The output characteristics of conventional tDCS, tACS, and tPCS techniques are well below those of most FDA cleared devices, including devices that are available OTC and those intended for stimulation on the head. This engineering analysis demonstrates that with regard to output performance and standing regulation, the availability of tDCS, tACS, or tPCS to the public would not introduce risk, provided such devices are responsibly manufactured and legally marketed. In Part 3, we develop voluntary manufacturer guidance for limited output tES that is aligned with current regulatory standards. Based on established medical engineering and scientific principles, we outline a robust and transparent technical framework for ensuring limited output tES devices are designed to minimize risks, while also supporting access and innovation. Alongside applicable medical and government activities, this voluntary industry standard (LOTES-2017) further serves an important role in supporting informed decisions by the public.

Mechanisms and Effects of Transcranial Direct Current Stimulation.

The US Air Force Office of Scientific Research convened a meeting of researchers in the fields of neuroscience, psychology, engineering, and medicine to discuss most pressing issues facing ongoing research in the field of transcranial direct current stimulation (tDCS) and related techniques. In this study, we present opinions prepared by participants of the meeting, focusing on the most promising areas of research, immediate and future goals for the field, and the potential for hormesis theory to inform tDCS research. Scientific, medical, and ethical considerations support the ongoing testing of tDCS in healthy and clinical populations, provided best protocols are used to maximize safety. Notwithstanding the need for ongoing research, promising applications include enhancing vigilance/attention in healthy volunteers, which can accelerate training and support learning. Commonly, tDCS is used as an adjunct to training/rehabilitation tasks with the goal of leftward shift in the learning/treatment effect curves. Although trials are encouraging, elucidating the basic mechanisms of tDCS will accelerate validation and adoption. To this end, biomarkers (eg, clinical neuroimaging and findings from animal models) can support hypotheses linking neurobiological mechanisms and behavioral effects. Dosage can be optimized using computational models of current flow and understanding dose-response. Both biomarkers and dosimetry should guide individualized interventions with the goal of reducing variability. Insights from other applied energy domains, including ionizing radiation, transcranial magnetic stimulation, and low-level laser (light) therapy, can be prudently leveraged.

Chronic Pain in Children and Adolescents: Diagnosis and Treatment of Primary Pain Disorders in Head, Abdomen, Muscles and Joints.

Primary pain disorders (formerly "functional pain syndromes") are common, under-diagnosed and under-treated in children and teenagers. This manuscript reviews key aspects which support understanding the development of pediatric chronic pain, points to the current pediatric chronic pain terminology, addresses effective treatment strategies, and discusses the evidence-based use of pharmacology. Common symptoms of an underlying pain vulnerability present in the three most common chronic pain disorders in pediatrics: primary headaches, centrally mediated abdominal pain syndromes, and/or chronic/recurrent musculoskeletal and joint pain. A significant number of children with repeated acute nociceptive pain episodes develop chronic pain in addition to or as a result of their underlying medical condition "chronic-on-acute pain." We provide description of the structure and process of our interdisciplinary, rehabilitative pain clinic in Minneapolis, Minnesota, USA with accompanying data in the treatment of chronic pain symptoms that persist beyond the expected time of healing. An interdisciplinary approach combining (1) rehabilitation; (2) integrative medicine/active mind-body techniques; (3) psychology; and (4) normalizing daily school attendance, sports, social life and sleep will be presented. As a result of restored function, pain improves and commonly resolves. Opioids are not indicated for primary pain disorders, and other medications, with few exceptions, are usually not first-line therapy.

Spirituality: an overlooked predictor of placebo effects?

Empirical findings have identified spirituality as a potential health resource. Whereas older research has associated such effects with the social component of religion, newer conceptualizations propose that spiritual experiences and the intrapersonal effects that are facilitated by regular spiritual practice might be pivotal to understanding potential salutogenesis. Ongoing studies suggest that spiritual experiences and practices involve a variety of neural systems that may facilitate neural 'top-down' effects that are comparable if not identical to those engaged in placebo responses. As meaningfulness seems to be both a hallmark of spirituality and placebo reactions, it may be regarded as an overarching psychological concept that is important to engaging and facilitating psychophysiological mechanisms that are involved in health-related effects. Empirical evidence suggests that spirituality may under certain conditions be a predictor of placebo response and effects. Assessment of patients' spirituality and making use of various resources to accommodate patients' spiritual needs reflect our most current understanding of the physiological, psychological and socio-cultural aspects of spirituality, and may also increase the likelihood of eliciting self-healing processes. We advocate the position that a research agenda addressing responses and effects of both placebo and spirituality could therefore be (i) synergistic, (ii) valuable to each phenomenon on its own, and (iii) contributory to an extended placebo paradigm that is centred around the concept of meaningfulness.

The therapeutic milieu reconceptualized for the 21st century.

The notion of the therapeutic milieu has come under fire for lack of relevance to current inpatient psychiatric care environments. Yet, in different fields of health care, scholars are suggesting a need to build healing environments. A view of the therapeutic milieu as an optimal healing environment based on continuous healing relationships, patient-centered care, safety as a systems priority, and cooperation among clinicians provides a framework to organize care in a holistic manner that supports positive health outcomes. This approach provides a platform for nurses and other clinicians to expand the view of a milieu traditionally limited to the unit environment to one that includes a broad systems context.

Maldynia: chronic pain as illness, and the need for complementarity in pain care.

An expanding epistemology has generated enhanced understanding of the mechanistic basis and existential impact of pain as a complexity-based systems event, and compels the need to develop diagnostic and therapeutic approaches that reflect this progressive knowledge. The basic and clinical sciences, humanities and the experiential narratives of patients all contribute essential lenses through which we can examine and de-mystify the enigma of persistent pain. It is only through the combination of distinct domains of knowledge that we can both comprehend pain as a dysfunction of the dynamical, non-linear adaptability of the nervous system, and at the same time apprehend the manifestations of these changes within the networked-hierarchy of interacting systems that is the patient as person. These are concepts that are inherent to, and derived from complexity theory, and the use of a complexity-based model of pain may be important to fully reconcile the notions of disease and illness, and fit these within a more encompassing framework. Thus, the study of pain conjoins neuroscience to the burgeoning discourse of neurophilosophy, and in so doing, may allow a more thorough dialectical approach to addressing concepts of disease-illness, brain-mind, and ethical dimensions of care.

On the therapeutic viability of peripheral nerve stimulation for ilioinguinal neuralgia: putative mechanisms and possible utility.

Injury to the ilioinguinal nerve commonly follows during lower abdominal and pelvic surgery, especially with inguinal hernia repair, appendectomy, and hysterectomy. Other potential causes include low abdominal blunt trauma, iliac crest bone graft, psoas abscess, Pott's disease, and prolonged wearing of abdominally constrictive clothing. The actual incidence of ilioinguinal neuralgia is uncertain, as reported percentage ranges between 12% and 62%. Prompt and accurate diagnosis is critical, and appropriate treatments range from conservative pharmacologic management with nonopioid (eg, gabapentin, topiramate) as well as opioid agents, to surgical neurectomy of the proximal portion of the ilioinguinal nerve. Pharmacological treatment is frequently unsuccessful (particularly if delayed) and while surgery is successful in approximately 73% of cases, it can result in problematic paresthesias, and pain may continue to persist in some patients. Thus, minimally invasive techniques, such as peripheral nerve stimulation, may be viable in those patients who are refractory to pharmacological management, as an option to surgery, and who have not gained satisfactory pain relief through surgical intervention. We present three cases of successful pain control of ilioinguinal neuralgia with peripheral nerve stimulation. These cases demonstrate the potential benefits of neurostimulation including durable effective pain relief and decreased use of medication. Putative mechanisms of effect(s) and caveats for continued research to inform prudent employment of this technique are presented.

Mind-body therapies for headache.

Headache is one of the most common and enigmatic problems encountered by family physicians. Headache is not a singular entity, and different pathologic mechanisms are involved in distinct types of headache. Most types of headache involve dysfunction of peripheral or central nociceptive mechanisms. Mind-body therapies such as biofeedback, cognitive behavior therapy, hypnosis, meditation, and relaxation training can affect neural substrates and have been shown to be effective treatments for various types of headache. Meta-analyses of randomized controlled trials show that the use of mind-body therapies, alone or in combination, significantly reduces symptoms of migraine, tension, and mixed-type headaches. Side effects generally are minimal and transient.

Efficacy of selected complementary and alternative medicine interventions for chronic pain.

Complementary and alternative medicine (CAM) is a group of diverse medical and healthcare systems, therapies, and products that are not presently considered part of conventional medicine. This article provides an up-to-date review of the efficacy of selected CAM modalities in the management of chronic pain. Findings are presented according to the classification system developed by the National Institutes of Health National Center for Complementary and Alternative Medicine (formerly Office of Alternative Medicine) and are grouped into four domains: biologically based medicine, energy medicine, manipulative and body-based medicine, and mind-body medicine. Homeopathy and acupuncture are discussed separately as "whole or professionalized CAM practices." Based on the guidelines of the Clinical Psychology Division of the American Psychological Association, findings indicate that some CAM modalities have a solid track record of efficacy, whereas others are promising but require additional research. The article concludes with recommendations to pain practitioners.

Neural and cognitive basis of spiritual experience: biopsychosocial and ethical implications for clinical medicine.

The role of patient spirituality and spiritual/liminal experience(s; SE) in the clinical setting has generated considerable equivocality within the medical community. Spiritual experience(s), characterized by circumstance, manifestation, and interpretation, reflect patients' explanatory models. We seek to demonstrate the importance of SE to clinical medicine by illustrating biological, cognitive, and psychosocial domains of effect. Specifically, we address where in the brain these events are processed and what types of neural events may be occurring. We posit that existing evidence suggests that SE can induce both intermediate level processing (ILP) to generate attentional awareness (ie, "consciousness of") effects and perhaps nonintermediate level processing to generate nonattentive, subliminal (ie, "state of") consciousness effects. Recognition of neural and cognitive mechanisms is important to clinicians' understanding of the biological basis of noetic, salutogenic, and putative physiologic effects. We posit that neurocognitive mechanisms, fortified by anthropologic and social contexts, led to the incorporation of SE-evoked behaviors into health-based ritual(s) and religious practice(s). Thus, these experiences not only exert biological effects but may provide important means for enhancing patients' locus of control. By recognizing these variables, we advocate clinicians to act within an ethical scope of practice as therapeutic and moral agents to afford patients resources to accommodate their specific desire(s) and/or need(s) for spiritual experiences, in acknowledgement of the underlying mechanisms and potential outcomes that may be health promotional.

Challenges to complementary and alternative medical research: focal issues influencing integration into a cancer care model.

Complementary and alternative therapies are increasingly used by cancer patients for palliative and postcancer preventive and/or wellness care. It is critical that evidence-based models be employed to both provide information for patients' use and informed consent and for physicians to advise patients and assess relative risk:benefit ratios of using specific complementary and alternative medicine (CAM) approaches within the cancer care paradigm. Research models for biomedicine have been somewhat limited when applied to broader, more holistic conceptualizations of health common to many forms of CAM. Thus, while numerous challenges to studying CAM exist, a fundamental question is not just what CAM practices should be studied but how CAM should be studied. The authors propose a model that emphasizes methodologic rigor yet approaches CAM research according to relative levels of evidence, meaning, and context, ranging from experimental, quantitative studies of mechanism to qualitative, observational studies of noetic/salutogenic variables. Responsibility for training researchers prepared to meet such challenges rests on both CAM and mainstream academic institutions, and care must be taken to avoid philosophical and practical pitfalls that might befall a myopic perspective of integration.

Integrating Chinese traditional medicine into a U.S. public health paradigm.

Chinese traditional medicine (CTM) is a health care system with an extensive history of practical clinical experience. The foundation of CTM, while relatively simple, is substantively different from much of allopathic medicine. Such differences are difficult to explain using a Western medical vocabulary, and extend beyond linguistic foundations. This proves challenging when trying to identify appropriate teaching and research methods that are sensitive to the CTM paradigm and yet relevant to a public health orientation. Given the increased use of CTM, it becomes important to address possibilities that would ensure successful integration of CTM into a public health framework. We propose a model in which both CTM and biomedical clinical services could be offered to provide diverse, yet truly integrative, therapeutic approaches. Within this model, it is critical to enhance reciprocal educational and research-directed opportunities for both CTM practitioners and allopathic clinicians. Considerable responsibility rests upon academic institutions in becoming proactive in developing and implementing educational curricula and research programs that illustrate more effectively the potential bilateral benefit(s), limitations, and, ultimately, roles that CTM and biomedical approaches may assume within an integrative system of care.

Complementary and alternative medicine in mainstream public health: a role for research in fostering integration.

In light of the increased utilization of complementary and alternative medicine (CAM) in recent years, there is an increased possibility that CAM approaches could prove to be important factors in public health, particularly if used within an integrative framework together with mainstream medicine. There exists a defined need for research to explore the integration of conventional health care and CAM approaches, as well as define mechanisms of CAM-based therapies to facilitate such integration. Essential to these goals is the accumulation of a database derived from outcomes-based clinical and basic science investigations. We posit that that CAM clinicians need to be more thoroughly trained as researchers, skilled in developing and recording results of pragmatic studies that could provide credible evidence for the use of CAM in the public sector health care. It is proposed that this may be best achieved through a three-tiered system in which (1) clinician-scientists of both mainstream and alternative disciplines recognize the value of research designed to foster such integration; (2) educational and health care institutions must develop academic and clinical training programs that examine and delineate each disciplines' respective strengths and weaknesses; and (3) such programs are attractive to, and receive continued extramural subsidy. In the broadest sense, such a paradigmatic approach to CAM integration could create a common basis for scientific dialogue, encourage exchanges between medical communities, and establish policies for the development of a true multidisciplinary health care cooperative that is consistent with the current public health model.