Patterns of CAG repeat instability in the central nervous system and periphery in Huntington's disease and in spinocerebellar ataxia type 1.

The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.

Human Dermal Allograft Superior Capsule Reconstruction With Graft Length Determined at Glenohumeral Abduction Angles of 20° and 40° Decreases Joint Translation and Subacromial Pressure Without Compromising Range of Motion: A Cadaveric Biomechanical Study.

PURPOSE: To compare the biomechanical effects of superior capsule reconstruction (SCR) graft fixation length determined at 20° and 40° of glenohumeral (GH) abduction. METHODS: Humeral translation, rotational range of motion (ROM), and subacromial contact pressure were quantified at 0°, 30°, and 60° of GH abduction in the scapular plane in 6 cadaveric shoulders for the following states: intact, massive rotator cuff tear, SCR with dermal allograft fixed at 20° of GH abduction (SCR 20), and SCR with dermal allograft fixed at 40° of GH abduction (SCR 40). Statistical analysis was conducted using a repeated-measures analysis of variance and a paired t test (P < .05). RESULTS: A massive cuff tear significantly increased total ROM compared with the intact state at 0° and 60° of abduction. SCR 20 or SCR 40 did not affect ROM. Compared with the intact state, the massive cuff tear model significantly increased superior translation by an average of 4.6 ± 0.5 mm in 9 of 12 positions (P ≤ .002). Both SCR 20 and SCR 40 reduced superior translation compared with the massive cuff tear model (P < .05); however, SCR 40 significantly decreased superior translation compared with SCR 20 at 0° of abduction (P ≤ .046). Peak subacromial pressure for the massive cuff tear model increased by an average of 486.8 ± 233.9 kPa relative to the intact state in 5 of 12 positions (P ≤ .037). SCR 20 reduced peak subacromial pressure in 2 of 12 positions (P ≤ .012), whereas SCR 40 achieved this in 6 of 12 positions (P ≤ .024). CONCLUSIONS: SCR with dermal allograft fixed at 20° or 40° of GH abduction decreases GH translation and subacromial pressure without decreasing ROM. CLINICAL RELEVANCE: With an increasing abduction angle for graft fixation, the medial-to-lateral graft length is decreased and the graft tension is effectively increased. Surgeons may increase shoulder stability without restricting ROM by fixing the graft at higher abduction angles. However, surgeons should remain cognizant of potential graft failure due to increased tension.

Ultra low doses and biological amplification: Approaching Avogadro's number.

This paper describes evidence establishing that ultra-low doses of diverse chemical agents at concentrations from 10-18 to 10-24 M (e.g., approaching and/or less than 1 atom or molecule of a substance/cell based on Avogadro's constant - 6.022×1023/mole) are capable of engaging receptor and intracellular signaling systems to elicit reproducible effects in a variety of species, from unicellular organisms to humans. Multiple experimental studies have shown that only one or very few molecules are needed to activate a cell and/or entire organism via cascade(s) of amplification mechanisms and processes. For example, ultra-low dose ligand exposure was able to activate both an individual cell, and ~3000 to 25,000 neighboring cells on average, by about 50%. Such activation of cells and whole organisms typically displayed hormetic-biphasic dose responses. These findings indicate that numerous, diverse phylogenetic systems have evolved highly sensitive detection and signaling mechanisms to enhance survival functions, such as defense against infectious agents, responses to diverse types of pheromone communications (e.g., alarm, sexual attraction), and development of several types of cellular protection/resilience processes. This suggests that ultra-low dose effects may be far more common than have been recognized to date. We posit that such findings have important implications for evolutionary theory, ecological and systems biology, and clinical medicine.

Cytotoxicity models of Huntington's disease and relevance of hormetic mechanisms: A critical assessment of experimental approaches and strategies.

This paper assesses in vivo cytotoxicity models of Huntington's disease (HD). Nearly 150 agents were found to be moderately to highly effective in mitigating the pathological sequelae of cytotoxic induction of HD features in multiple rodent models. Typically, rodents are treated with a prospective HD-protective agent before, during, or after the application of a chemical or transgenic process for inducing histopathological and behavioral symptoms of HD. Although transgenic and knockout rodent models (1) display relatively high construct and face validity, and (2) are ever more routinely employed to mimic genetic-to-phenotypic expression of HD features, toxicant models are also often employed, and have served as valuable test beds for the elucidation of biochemical processes and discovery of therapeutic targets in HD. Literature searches of the toxicant HD rodent models yielded nearly 150 agents that were moderately to highly effective in mitigating pathological sequelae in multiple mouse and rat HD models. Experimental models, study designs, and exposure protocols (e.g., pre- and post-conditioning) used in testing these agents were assessed, including dosing strategies, endpoints, and dose-response features. Hormetic-like biphasic dose responses, chemoprotective mechanisms, and the translational relevance of the preclinical studies and their therapeutic implications are critically analyzed in the present report. Notably, not one of the 150 agents that successfully delayed onset and progression of HD in the experimental models has been successfully translated to the treatment of humans in a clinical setting. Potential reasons for these translational failures are (1) the inadequacy of dose-response analyses and subsequent lack of useful dosing data; (2) effective rodent doses that are too high for safe human application; (3) key differences between the experimental models and humans in pharmacokinetic/pharmacodynamic features, ages and routes of agent administration; (4) lack of robust pharmacokinetic, mechanistic or systematic approaches to probe novel treatment strategies; and (5) inadequacies of the chemically induced HD model in rats to mimic accurately the complex genetic and developmental origin and progression of HD in humans. These deficiencies need to be urgently addressed if pharmaceutical agents for the treatment of HD are going to be successfully developed in experimental models and translated with fidelity to the clinic.

Hormetic approaches to the treatment of Parkinson's disease: Perspectives and possibilities.

Age-related changes in the brain reflect a dynamic interaction of genetic, epigenetic, phenotypic, and environmental factors that can be temporally restricted or more longitudinally present throughout the lifespan. Fundamental to these mechanisms is the capacity for physiological adaptation through modulation of diverse molecular and biochemical signaling occurring from the intracellular to the network-systemic level throughout the brain. A number of agents that affect the onset and progression of Parkinson's disease (PD)-like effects in experimental models exhibit temporal features, and mechanisms of hormetic dose responses. These findings have particular significance since the hormetic dose response describes the amplitude and range of potential therapeutic effects, thereby affecting the design and conduct of studies of interventions against PD (and other neurodegenerative diseases), and may also be important to a broader consideration of hormetic processes in resilient adaptive responses that might afford protection against the onset and/or progression of PD and related disorders.

Hormesis mediates dose-sensitive shifts in macrophage activation patterns.

The activation or polarization of macrophages to pro- or anti-inflammatory states evolved as an adaptation to protect against a spectrum of biological threats. Such an adaptation engages pro-oxidative mechanisms and enables macrophages to neutralize and kill threatening organisms (e.g., viruses, bacteria, mold), limit cancerous growths, and enhance recovery and repair processes. The present study demonstrates that (1) many diverse pharmacological, chemical and physical agents can mediate a dose/concentration-dependent shift between pro- and anti-inflammatory activation states, and (2) these shifts in activation states display biphasic dose-response relationships that are characteristic of hormesis. This study also reveals that preconditioning-another form of hormesis-similarly mediates tissue protection by the polarization of macrophages, but in this case, towards an anti-inflammatory phenotype. This assessment supports the generalizability and significance of hormesis in biology, medicine, and public health and further extends it to encompass the hormetic activation of macrophages.

Elemental mercury neurotoxicity and clinical recovery of function: A review of findings, and implications for occupational health.

This paper assessed approximately 30 studies, mostly involving occupationally exposed subjects, concerning the extent to which those who developed elemental mercury (Hg)-induced central and/or peripheral neurotoxicities from chronic or acute exposures recover functionality and/or performance. While some recovery occurred in the vast majority of cases, the extent of such recoveries varied considerably by individual and endpoint. Factors accounting for the extensive inter-individual variation in toxicity and recovery were not specifically assessed such as age, gender, diet, environmental enrichment, chelation strategies and dose-rate. While the data indicate that psychomotor endpoints often show substantial and relatively rapid (i.e., 2-6 months) recovery and that neuropsychological endpoints display slower and less complete recovery, generalizations are difficult due to highly variable study designs, use of different endpoints measured between studies, different Hg exposures based on blood/urine concentrations and Hg dose-rates, the poor capacity for replicating findings due to the unpredictable/episodic nature of harmful exposures to elemental Hg, and the inconsistency of the initiation of studies after induced toxicities and the differing periods of follow up during recovery periods. Finally, there is strikingly limited animal model literature on the topic of recovery/reversibility of elemental Hg toxicity, a factor which significantly contributes to the overall marked uncertainties for predicting the rate and magnitude of recovery and the factors that affect it.

Looking Ahead: The Importance of Views, Values, and Voices in Neuroethics-Now.

The body-to-head transplant (BHT) planned to be undertaken later this year at China's Harbin Medical University by neurosurgeons Sergio Canavero and Xiaoping Ren has attracted considerable attention and criticism. The intended operation gives rise to philosophical queries about the body-brain-mind relationship and nature of the subjective self; technical and ethical issues regarding the scientific soundness, safety, and futility of the procedure; the adequacy of prior research; and the relative merit, folly, and/or danger of forging new boundaries of what is biomedically possible. Moreover, that this procedure, which has been prohibited from being undertaken in other countries, has been sanctioned in China brings into stark relief ways that differing social and political values, philosophies, ethics, and laws can affect the scope and conduct of research. Irrespective of whether the BHT actually occurs, the debate it has generated reveals and reflects both the evermore international enterprise of brain science, and the need for neuroethical discourse to include and appreciate multicultural views, values, and voices.

Hormesis, cellular stress response and neuroinflammation in schizophrenia: Early onset versus late onset state.

Abnormal redox homeostasis and oxidative stress have been proposed to play a role in the etiology of several neuropsychiatric spectrum disorders. Emerging interest has recently focused on markers of oxidative stress and neuroinflammation in schizophrenic spectrum disorders, at least in particular subgroups of patients. Altered expression of genes related to oxidative stress, oxidative damage to DNA, protein and lipids, as well as reduced glutathione levels in central and peripheral tissues could act synergistically, and contribute to the course of the disease. Herein, we discuss cellular mechanisms that may be operative in neuroinflammation and contributory to schizophrenia. We address modulation of endogenous cellular defense mechanisms as a potentially innovative approach to therapeutics for schizophrenia, and other neuropsychiatric conditions that are associated with neuroinflammation. Specifically, we discuss the emerging role of heme oxygenase as prominent member of neuroprotective network in redox stress responsive mechanisms, as well as the importance of glutathione relevant in schizophrenia pathophysiology. Finally we introduce the hormetic dose response concept as relevant and important to neuroprotection, and review hormetic mechanisms as possible approaches to manipulation of neuroinflammatory targets that may be viable for treating schizophrenia spectrum disorders. © 2016 Wiley Periodicals, Inc.

Research Domain Criteria as Psychiatric Nosology.

Diagnostic classification systems in psychiatry have continued to rely on clinical phenomenology, despite limitations inherent in that approach. In view of these limitations and recent progress in neuroscience, the National Institute of Mental Health (NIMH) has initiated the Research Domain Criteria (RDoC) project to develop a more neuroscientifically based system of characterizing and classifying psychiatric disorders. The RDoC initiative aims to transform psychiatry into an integrative science of psychopathology in which mental illnesses will be defined as involving putative dysfunctions in neural nodes and networks. However, conceptual, methodological, neuroethical, and social issues inherent in and/or derived from the use of RDoC need to be addressed before any attempt is made to implement their use in clinical psychiatry. This article describes current progress in RDoC; defines key technical, neuroethical, and social issues generated by RDoC adoption and use; and posits key questions that must be addressed and resolved if RDoC are to be employed for psychiatric diagnoses and therapeutics. Specifically, we posit that objectivization of complex mental phenomena may raise ethical questions about autonomy, the value of subjective experience, what constitutes normality, what constitutes a disorder, and what represents a treatment, enablement, and/or enhancement. Ethical issues may also arise from the (mis)use of biomarkers and phenotypes in predicting and treating mental disorders, and what such definitions, predictions, and interventions portend for concepts and views of sickness, criminality, professional competency, and social functioning. Given these issues, we offer that a preparatory neuroethical framework is required to define and guide the ways in which RDoC-oriented research can-and arguably should-be utilized in clinical psychiatry, and perhaps more broadly, in the social sphere.

Neuroscience Fiction as Eidolá: Social Reflection and Neuroethical Obligations in Depictions of Neuroscience in Film.

Neuroscience and neurotechnology are increasingly being employed to assess and alter cognition, emotions, and behaviors, and the knowledge and implications of neuroscience have the potential to radically affect, if not redefine, notions of what constitutes humanity, the human condition, and the "self." Such capability renders neuroscience a compelling theme that is becoming ubiquitous in literary and cinematic fiction. Such neuro-SciFi (or "NeuroS/F") may be seen as eidolá: a created likeness that can either accurately-or superficially, in a limited way-represent that which it depicts. Such eidolá assume discursive properties implicitly, as emotionally salient references for responding to cultural events and technological objects reminiscent of fictional portrayal; and explicitly, through characters and plots that consider the influence of neurotechnological advances from various perspectives. We argue that in this way, neuroS/F eidolá serve as allegorical discourse on sociopolitical or cultural phenomena, have power to restructure technological constructs, and thereby alter the trajectory of technological development. This fosters neuroethical responsibility for monitoring neuroS/F eidolá and the sociocultural context from which-and into which-the ideas of eidolá are projected. We propose three approaches to this: evaluating reciprocal effects of imaginary depictions on real-world neurotechnological development; tracking changing sociocultural expectations of neuroscience and its uses; and analyzing the actual process of social interpretation of neuroscience to reveal shifts in heuristics, ideas, and attitudes. Neuroethicists are further obliged to engage with other discourse actors about neuroS/F interpretations to ensure that meanings assigned to neuroscientific advances are well communicated and more fully appreciated.

Major pathogenic mechanisms in vascular dementia: Roles of cellular stress response and hormesis in neuroprotection.

Vascular dementia (VaD), considered the second most common cause of cognitive impairment after Alzheimer disease in the elderly, involves the impairment of memory and cognitive function as a consequence of cerebrovascular disease. Chronic cerebral hypoperfusion is a common pathophysiological condition frequently occurring in VaD. It is generally associated with neurovascular degeneration, in which neuronal damage and blood-brain barrier alterations coexist and evoke beta-amyloid-induced oxidative and nitrosative stress, mitochondrial dysfunction, and inflammasome- promoted neuroinflammation, which contribute to and exacerbate the course of disease. Vascular cognitive impairment comprises a heterogeneous group of cognitive disorders of various severity and types that share a presumed vascular etiology. The present study reviews major pathogenic factors involved in VaD, highlighting the relevance of cerebrocellular stress and hormetic responses to neurovascular insult, and addresses these mechanisms as potentially viable and valuable as foci of novel neuroprotective methods to mitigate or prevent VaD. © 2016 Wiley Periodicals, Inc.

Commentary: The Value of Patient Benefit: Consideration of Framing Contingencies to Guide the Ethical Use of DBS-a Case Analysis.

Here we have a case in which (1) the outcome(s) for the patient do not comport with the projected-or initially defined-outcomes of the research study, and (2) these outcomes represent cognitive and behavioral effects that are positively interpreted by the patient, but not by the patient's immediate family. The 6Cs approach, which frames the technique or technology-and its effects-within defined considerations of domains and dimensions, can be used as part of a multistep approach to addressing issues arising from the use of neurotechnology. 1 The approach recommends that the medical team consider the following domains and dimensions when engaging neuroethical analyses: • The capacities and limitations of current neuroscience and technology (neuroS/T), and the capacity of the patient • The consequences incurred by neuroS/T on recipients, families, and society in the short, intermediate, and long term • The character of the recipient (e.g., patterns of cognition, emotion, and behavior) affected by neuroS/T • The continuity of research and clinical care • The contexts of need and value that influence the use or nonuse of neuroS/T • Consent through provision of the most information possible 2.

Don't Ask a Neuroscientist about Phases of the Moon.

Ongoing developments in neuroscientific techniques and technologies-such as neuroimaging-offer potential for greater insight into human behavior and have fostered temptation to use these approaches in legal contexts. Neuroscientists are increasingly called on to provide expert testimony, interpret brain images, and thereby inform judges and juries who are tasked with determining the guilt or innocence of an individual. In this essay, we draw attention to the actual capabilities and limitations of currently available assessment neurotechnologies and examine whether neuroscientific evidence presents unique challenges to existing frameworks of evidence law. In particular, we focus on (1) fundamental questions of relevance and admissibility that can and should be posed before the tests afforded in Daubert v. Merrill Dow Pharmaceuticals or Frye v. U.S. are applied and (2) how these considerations fit into the broader contexts of criminal law. We contend that neuroscientific evidence must first be scrutinized more heavily for its relevance, within Daubert and Federal Rule of Evidence 702, to ensure that the right questions are asked of neuroscientists, so as to enable expert interpretation of neuroscientific evidence within the limits of their knowledge and discipline that allows the judge or jury to determine the facts at issue in the case. We use the analogy provided by the Daubert court of an expert on the phases of the moon testifying to an individual's behavior on a particular night to ensure that we are, in fact, asking the neuroscientific expert the appropriate question.

Neuroethics beyond Normal.

An integrated and principled neuroethics offers ethical guidelines able to transcend conventional and medical reliance on normality standards. Elsewhere we have proposed four principles for wise guidance on human transformations. Principles like these are already urgently needed, as bio- and cyberenhancements are rapidly emerging. Context matters. Neither "treatments" nor "enhancements" are objectively identifiable apart from performance expectations, social contexts, and civic orders. Lessons learned from disability studies about enablement and inclusion suggest a fresh way to categorize modifications to the body and its performance. The term "enhancement" should be broken apart to permit recognition of enablements and augmentations, and kinds of radical augmentation for specialized performance. Augmentations affecting the self, self-worth, and self-identity of persons require heightened ethical scrutiny. Reversibility becomes the core problem, not the easy answer, as augmented persons may not cooperate with either decommissioning or displacement into unaccommodating societies. We conclude by indicating how our four principles of self-creativity, nonobsolescence, empowerment, and citizenship establish a neuroethics beyond normal that is better prepared for a future in which humans and their societies are going so far beyond normal.