Faculty Bibliography

Objective: To illustrate progression in motor symptoms of idiopathic Parkinson's disease (PD) in individual patients who have had regular Alexander Technique (AT) lessons for at least 3 years. Background: AT is an educational approach that teaches attention and inhibition to change functional patterns, reduce rigidity, and improve balance and efficiency during exercise and activities of daily living (ADLs). Lessons involve verbal instructions and handson guidance to teach self-management strategies that improve and, as much as possible, restore functional movement patterns, enabling the person with PD to participate in ADLs with minimal interference from PD symptoms. Preliminary data: Candace Cox previously presented a single case study at the 3rd World Parkinson Congress in Montreal in 2013. (Cox, 2013). Diagnosed with PD and prescribed medication in 2003, the patient then had AT lessons for 10 years. Independent, qualified physiotherapists assessed progress of the patient's PD symptoms using the Berg Balance Scale, Timed Up and Go (TUG) and UPDRS III (Motor Subscale) at regular intervals. AT lessons improved range and control of motion and enabled the patient to learn and apply new strategies in sitting, standing, walking, and reaching. Objectively measured symptom severity remained low ten years after diagnosis. (Figure presented) Approach: Using the method of Cox (2013), we will present case studies of 10 PD patients with at least 3 years of AT training. We will compare these to typical progression (as defined by Williams 2012; Mari 2012). Each case study will identify whether the subject initiated AT training before or after diagnosis, and the duration, form (i.e. group or private) and frequency of AT training. Subjective survey responses from subjects, and from their care partners if applicable, will also be presented. Conclusion: AT shows promise as a long-term self-management approach to reduce PD motor symptoms and maintain an active life

Diagnostic formulations attempt to impose order on the messy reality of psychopathological phenomena. By doing this, so their advocates argue, they provide both the platform necessary for systematic scientific study, and, crucially, the bridge of shared terms and concepts vital if psychiatric science is to be truly translational; where scientific endeavour is guided by clinical priorities and, in-turn, scientific findings innovate clinical practice. The diagnostic schemes we currently work with, taking DSM-5 as the obvious case, are the product of an interesting historical process of ongoing revision - at the same time pragmatic and scientific. On the one hand, it is a process both anchored firmly in historical precedent and constrained by the practical needs of clinicians, patients and health insurance companies. On the other hand, it is a process open to new empirical data about how to best cluster symptomatic expressions and differentiate clinical presentations - so that over historical time diagnostic categories achieve an increasingly accurate mapping of the taxonomy (i.e., underlying structure), and related pathophysiology, of psychiatric phenomenon. Resolving the inevitable tensions that arise when trying to reconcile these pragmatic (economic and professional) and scientific priorities has proved to be both challenging and contentious. The study of heterogeneity as exemplified by the articles highlighted in this editorial indicate a range of different approaches that can be effectively used to refine psychiatric taxonomies by incorporating developmental and pathophysiological data to help identify new putative subtypes of potential therapeutic significance.

The brain is subject to dramatic developmental processes during the prenatal period. Nevertheless, information about the development of functional brain networks during gestation is scarce. Until recently it has not been possible to probe function in the living human fetal brain. Advances in functional MRI have changed the paradigm, making it possible to measure spontaneous activity in the fetal brain and to cross-correlate functional signals to attain information about neural connectional architecture across human gestation. We summarize the earliest MRI studies of fetal neural functional connectivity and highlight unique challenges and limitations inherent in the technique. In addition, we discuss future directions to unlock the potential of fetal brain functional MRI research.

Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.

Perfluoroalkyl substances (PFAS) were shown to be immunotoxic in laboratory animals. There is some epidemiological evidence that PFAS exposure is inversely associated with vaccine-induced antibody concentration. We examined immune response to vaccination with FluMist intranasal live attenuated influenza vaccine in relation to four PFAS (perfluorooctanoate, perfluorononanoate, perfluorooctane sulfonate, perfluorohexane sulfonate) serum concentrations among 78 healthy adults vaccinated during the 2010-2011 influenza season. We measured anti-A H1N1 antibody response and cytokine and chemokine concentrations in serum pre-vaccination, 3 days post-vaccination, and 30 days post-vaccination. We measured cytokine, chemokine, and mucosal IgA concentration in nasal secretions 3 days post-vaccination and 30 days post-vaccination. Adults with higher PFAS concentrations were more likely to seroconvert after FluMist vaccination as compared to adults with lower PFAS concentrations. The associations, however, were imprecise and few participants seroconverted as measured either by hemagglutination inhibition (9%) or immunohistochemical staining (25%). We observed no readily discernable or consistent pattern between PFAS concentration and baseline cytokine, chemokine, or mucosal IgA concentration, or between PFAS concentration and change in these immune markers between baseline and FluMist-response states. The results of this study do not support a reduced immune response to FluMist vaccination among healthy adults in relation to serum PFAS concentration. Given the study's many limitations, however, it does not rule out impaired vaccine response to other vaccines or vaccine components in either children or adults.

BACKGROUND:Rescue and recovery workers responding to the 2001 collapse of the World Trade Center (WTC) sustained exposures to toxic chemicals and have elevated rates of multiple morbidities. METHODS:Using data from the World Trade Center Health Program and the National Death Index for 2002-2011, we examined standardized mortality ratios (SMR) and proportional cancer mortality ratios (PCMR) with indirect standardization for age, sex, race, and calendar year to the U.S. general population, as well as associations between WTC-related environmental exposures and all-cause mortality. RESULTS:We identified 330 deaths among 28,918 responders (SMR 0.43, 95%CI 0.39-0.48). No cause-specific SMRs were meaningfully elevated. PCMRs were elevated for neoplasms of lymphatic and hematopoietic tissue (PCMR 1.76, 95%CI 1.06-2.75). Mortality hazard ratios showed no linear trend with exposure. CONCLUSIONS:Consistent with a healthy worker effect, all-cause mortality among responders was not elevated. There was no clear association between intensity and duration of exposure and mortality. Surveillance is needed to monitor the proportionally higher cancer mortality attributed to lymphatic/hematopoietic neoplasms.

BACKGROUND:Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are immunotoxic in laboratory studies. Human studies of immune effects are inconsistent. Using the US National Health and Nutrition Examination Survey (NHANES), we examined PFAS serum concentration and indicators of prevalent immune function among 12-19-y-old children. METHODS:In this cross-sectional study, we examined PFAS serum concentration in relation to measles, mumps, and rubella antibody concentrations in NHANES 1999-2000 and 2003-2004 (n = 1,191) and to allergic conditions and allergic sensitization in NHANES 2005-2006 (n = 640). RESULTS:In adjusted, survey-weighted models, a doubling of perfluorooctane sulfonate (PFOS) concentration among seropositive children was associated with a 13.3% (95% confidence interval (CI): -19.9, -6.2) decrease in rubella antibody concentration and a 5.9% decrease in mumps antibody concentration (95% CI: -9.9, -1.6). We observed no adverse association between exposure and current allergic conditions, including asthma. Children with higher PFOS concentration were less likely to be sensitized to any allergen (odds ratio (OR): 0.74; 95% CI: 0.58, 0.95). CONCLUSION/CONCLUSIONS:Increased exposure to several PFAS was associated with lower levels to mumps and rubella antibody concentrations, especially among seropositive individuals. These lower antibody concentrations may indicate a less robust response to vaccination or greater waning of vaccine-derived immunity over time.

UNLABELLED:Remission rates for Major Depressive Disorder (MDD) are low and unpredictable for any given antidepressant. No biological or clinical marker has demonstrated sufficient ability to match individuals to efficacious treatment. Biosignatures developed from the systematic exploration of multiple biological markers, which optimize treatment selection for individuals (moderators) and provide early indication of ultimate treatment response (mediators) are needed. The rationale and design of a multi-site, placebo-controlled randomized clinical trial of sertraline examining moderators and mediators of treatment response is described. The target sample is 300 participants with early onset (≤30 years) recurrent MDD. Non-responders to an 8-week trial are switched double blind to either bupropion (for sertraline non-responders) or sertraline (for placebo non-responders) for an additional 8 weeks. Clinical moderators include anxious depression, early trauma, gender, melancholic and atypical depression, anger attacks, Axis II disorder, hypersomnia/fatigue, and chronicity of depression. Biological moderator and mediators include cerebral cortical thickness, task-based fMRI (reward and emotion conflict), resting connectivity, diffusion tensor imaging (DTI), arterial spin labeling (ASL), electroencephalograpy (EEG), cortical evoked potentials, and behavioral/cognitive tasks evaluated at baseline and week 1, except DTI, assessed only at baseline. The study is designed to standardize assessment of biomarkers across multiple sites as well as institute replicable quality control methods, and to use advanced data analytic methods to integrate these markers. A Differential Depression Treatment Response Index (DTRI) will be developed. The data, including biological samples (DNA, RNA, and plasma collected before and during treatment), will become available in a public scientific repository. CLINICAL TRIAL REGISTRATION:Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC). Identifier: NCT01407094. URL: http://clinicaltrials.gov/show/NCT01407094.

Understanding heterogeneity in phenotypical characteristics, symptoms manifestations and response to treatment of subjects with psychiatric illnesses is a continuing challenge in mental health research. A long-standing goal of medical studies is to identify groups of subjects characterized with a particular trait or quality and to distinguish them from other subjects in a clinically relevant way. This paper develops and illustrates a novel approach to this problem based on a method of optimal-partitioning (clustering) of functional data. The proposed method allows for the simultaneous clustering of different populations (e.g., symptoms of drug and placebo treated patients) in order to identify prototypical outcome profiles that are distinct from one or the other treatment and outcome profiles common to the different treatments. The clustering results are used to discover potential treatment effect modifiers (i.e., moderators), in particular, moderators of specific drug effects and placebo response. A depression clinical trial is used to illustrate the method.