Frank Symons - US grants

Why some people with mental retardation and/or autism repeatedly and persistently injure themselves, some so severely to the point of tissue damage and often times permanent scarring, has remained a mystery eluding a single solution. Unraveling this mystery poses paradoxial biomedical and behavioral science questions and creates deeply troubling problems for practitioners and family members of affected individuals. Over the past decade, many cases of self-injurious behavior (SIB) have been treated successfully using behavioral interventions that teach communication and other functional skills. Practical problems of implementation, costs associated with long-term treatment, and cases with no clear social profile appearing about 1/3 of the time suggest, however, that there is still much to be learned about why people self-injure. Our overall goals are to improve treatment, refine diagnosis, and to clarify mechanisms underlying different forms of self-injury. Given the severity of self-injury, it is surprising that few of the models have examined in more detail the relation between variables common to SIB and the neurophysiology of pain regulation. The main objective of this project is to evaluate the validity of several of these variables as possible predictors of response to self-injury. Treatments will be based on the hypothesis that some forms of self-injury involve intense stimulation of body sites sufficient to elicit the release and receptor binding of endogenous opioid peptides. Accordingly, treatments will include transcutaneous electric nerve stimulation (TENS)(an opioid agonist treatment) or naltrexone (an opioid antagonist treatment). Predictors will include observationally- based measures of the environmental functions of self-injury, body site location and intensity of self-injury, and salivary baseline levels of three bioactive substances (substance P, metenkephalin, & cortisol). Following initial identification of subjects (age range 4-25) with mold to profound mental retardation and/or autism, our first aim is to observe and describe in detail how frequently self- injury occurs, what its duration and intensity is, and where on the body it is directed. Following this characterization, substance P, met-enkephalin, and cortisol will be noninvasively examined through saliva as markers for altered pain transmission and predictors of response to treatment. After screening and SIB subtyping (i.e., social, nonsocial, or mixed) 37 subjects whose self-injury is primarily nonsocial or mixed will be evaluated over a 16-week period with TENS and the opiate antagonist naltrexone for self-injury. Subjects whose self-injury is primarily socially motivated will be evaluated with TENS and the opiate antagonist naltrexone for self-injury. Subjects whose self-injury is primarily socially motivated will be evaluated with TENS and receive behavioral interventions through a technical assistance service delivery model. Three- and six-month follow-ups will be conducted for each subject.

It has long been assumed that early stereotyped behavior may function as a precursor to later self-injurious behavior in children with mental retardation and related developmental disabilities. Much of the speculation is focused on the possibility that some forms of early stereotyped behavior are shaped by successive approximation into self- injury through a process of differential reinforcement from primary caregivers. Face validity notwithstanding, this assumption has never been systematically studied. Consequently, it remains difficult to make statements with confidence about the early development of one of the most serious behavior problems afflicting children with mental retardation and related developmental disabilities. Our major goal is to begin systematic study of the correlates and progression of early aberrant stereotypies and self-injury. We assume that early identification of precursors and elucidation of behavioral mechanisms will lead to larger treatment studies designed to prevent or reduce the risk of later development of severe self-injury. In our preliminary work to date, we have identified a group of young children who are at high risk for developmental disability secondary to serious medical illness during infancy. Over half of our current sample (N=25) have some form of stereotyped or self-injurious behavior. The mean age of reported onset for stereotyped behavior was 26 months and for self-injury was 34 months. This suggests the possibility of a general sequencing with stereotypies preceding self-injury, however, the nature of this relation remains unclear. The children with stereotypies and self-injury had more large movements during infancy compared with the children without stereotypies and self-injury. Further study is needed to understand the nature of the relation between large motor movements during infancy and later stereotyped and/or self-injurious behavior. Our specific objective in this study is to prospectively follow a group of already identified medically fragile infants beginning at 18-months corrected age for a two- year period. infants will be directly observed at point of entry into the study and then quarterly for one-hour long sessions during structured and unstructured play conditions with primary caregivers. For each infant, prospectively collected data will be available on the amount of time hospitalized and the amount of technology required for their survival. These variables will be conceptualized as perinatal risk factors related to environmental restriction and examined in relation to infant large motor movements and subsequent stereotyped and self-injurious behavior. Two- way analysis of variance with repeated measures will be used to compare differences between infants grouped by the presence or absence of stereotypy and self-injury. Finally, child effects on caregiver interaction will be studied using lag sequential analysis and comparing sequential dependencies between caregiver responsivity over time to infants with and without stereotypy and self-injury.

DESCRIPTION (provided by applicant): Little is known about the sensory and neurobiological basis of nonsocially-mediated self-injurious behavior. In behavioral models of SIB, sensory mechanisms function as putative positive or negative automatic reinforcers but there is little evidence directly linking behavioral and biological mechanisms. Evidence from both clinical and animal studies of chronic pain and its behavioral sequelae supports the hypothesis that some forms of SIB may be regulated by altered pain mechanisms. An established body of literature and the investigator's preliminary data provide initial support for the sensory dysfunction and pain hypothesis of chronic nonsocial SIB and point to an important role for the peripheral and central mechanisms of pain in the expression of chronic nonsocial SIB. The purpose of the proposed study is to compare socially and nonsocially-mediated SIB cases on a set of behavioral and biological measures related to sensory function and pain behavior. The overall goal is to refine an integrative analysis of the behavioral and biological mechanisms underlying chronic nonsocial SIB. Towards this end, we have developed a set of behavioral and biological markers of injury and pain that can be reliably measured in persons with developmental disorders and SIB. Following a vertical research strategy, chronic SIB cases (N = 80) will be functionally subtyped by behavioral mechanism (i.e., social versus nonsocial mediation). Representative samples of each subject's SIB will be precisely measured for its form, frequency, intensity, and body location. Each subject will be further characterized using measures of behavioral expression of pain (facial action units), morphology (density of epidermal nerve fibers), and neurochemistry (substance P, cortisol). This study will provide the first opportunity to systematically investigate mechanisms specific to pain underlying chronic nonsocially-mediated SIB.

DESCRIPTION (provided by applicant): Goals: My research has dealt primarily with the behavioral mechanisms underlying chronic SIB among individuals with developmental disorders. A more complete understanding of the pathophysiology of SIB will require integrating our rich understanding of pain neurobiology and stress psychobiology with our emerging understanding of the role of early experience on multiple pain and stress-sensitive physiological systems. Research: During my R29 funding period, I extended the opioid model of SIB in line with clinical features suggestive of altered pain processing, formed collaborative relations, and began developing the necessary expertise allowing me to seek funding to test an integrative pain and stress model of SIB in adults. The purpose of the funded R01 is to compare socially and nonsocially-mediated SIB adult cases on a set of behavioral and biological measures related to sensory function, stress physiology, and pain behavior. Career Plan: The career development plan uses a translational research training framework as an organizing set of principles to guide research and training goals specific to new developments in neuroscience and behavioral genetics, integrating the wider research program of developmental psychopathology, and expanding the self- injury research agenda to embrace gene-environmental interplay and improve our understanding of individual vulnerability. Preliminary work and collaborative relations are described to support the need for release time to enhance my training and research into these related areas. The plan emphasizes the need to extend self- injury research to issues germane to pediatric and neurological research (i.e., pain regulation, high risk populations), and to include other systems important in the regulation of pain (i.e., peripheral and central transmission mechanisms), stress (i.e., the HPA axis), and the autonomic nervous system (i.e., fronto-limbic and autonomic circuitry). Specifically, I want to gain the expertise to test the following three preliminary hypotheses. First, there will be differences in hypothalamic-pituitary-adrenal (HPA) axis activity (cortisol) and sensory function (detection thresholds) in children with severe neurological impairment and self-injury compared with matched controls without self-injury (between group analyses). Second: the frequency and temporal sequencing of self-injury will be correlated with HPA axis activity and sensory function (within group analyses). Third, the relation between HPA axis activity, sensory function, and SIB will change over time such that the degree of dysregulation in the former predicts increasing severity in the latter (prospective analysis). Institution and Environment Commitment: The Department of Educational Psychology and the University of Minnesota are committed to this award and provide rich resources for my career development.

DESCRIPTION (provided by applicant): Little is known about the sensory and neurobiological basis of chronic self-injurious behavior (SIB) among individuals with intellectual and developmental disabilities (IDD). In behavioral models of SIB, sensory mechanisms function as putative positive or negative automatic reinforcers but there is little evidence directly linking behavioral and biological mechanisms. Evidence from both clinical and animal studies of chronic pain and its behavioral sequelae supports the hypothesis that some forms of SIB may be regulated by altered pain mechanisms. From our work and that of others, we know that pain can lead to SIB in this population but we know almost nothing about whether chronic SIB leads to pain and the resulting neuro-immune cascade of effects. An established body of preclinical and clinical literature and the investigator's preliminary data provide initial support for a working sensory dysfunction and neuropathic-pain like hypothesis of chronic SIB and point to an important role for the peripheral and central mechanisms of pain and inflammatory/immune activity. The purpose of this project is to begin testing a novel model of SIB in relation to chronic neuropathic-like pain due to inflammatory and immune system activation. We hypothesize that there will be a subgroup of individuals with chronic SIB that have significantly (a) altered peripheral sensory innveration, (b) increased inflammatory and immune activity, and (c) increased immune-mediated 'sickness'like behavior. A case-control design will be used to compare matched (age, gender, IQ) groups of children with IDD with (n = 40) and without SIB (n = 40). The groups will be compared on measures of (a) peripheral innervation (Aim 1), (b) inflammatory/immune cytokines and related peptides (Aim 2), and (c) functional indicators of 'sickness'-like behavior including adaptive/social behavior, sleeping/eating, and sensory reactivity and pain signs/symptoms as well as within SIB group comparisons of functional and structural variables (Aim 3). Our preliminary results suggest that, at least in the periphery, ongoing neuro-immune interactions may, in part, be related to the as of yet poorly understood pathophysiology of chronic self-injury. This study will provide the first opportunity to systematically investigate neuro-immune variables in relation to SIB among children with IDD.

DESCRIPTION (provided by applicant): This application addresses PA 10-006 Mechanisms, Models, Measurement, and Management in Pain Research (R01). The majority of children with cerebral palsy (CP) live with spasticity and spasticity-induced disabling chronic pain. One of the front-line treatments for spasticity involves surgically implanting a pump to intrathecally deliver baclofen (ITB). Doing so avoids the problems with orally administered baclofen but creates problems of its own including general surgical risks but also procedure specific issues such as cerebral spinal fluid (CSF) leaks and catheter malfunction leading to serious withdrawal complications. Thus, the procedure is not without risk, but on balance the evidence is tilted toward efficacy for spasticity outcomes by reducing spasticity. It is less clear, however, whether the chronic pain is also and always reduced. There are mixed and muddled results specific to pain outcomes; mixed because in some studies pain is reported to decrease but in others there is no apparent change, muddled because the majority of the studies are poorly designed with pain poorly measured and so the results are scientifically uncertain and clinically ambiguous. This specific problem - whether or not pain improves following ITB treatment - is part of a much broader general issue - whether we can use scientific advances from pain research to improve our clinical understanding of pain and disability among children with significant intellectual, motor, and communicative impairments associated with neurodevelopmental disorders. The overall goal of this application is to initiate a line of research with the primary objective of improving our scientific understanding of changes in chronic pain in response to treatment among children with significant neurodevelopmental disabilities. The specific purpose of this interdisciplinary translational proposal is to clarify the clinical ambiguity in pain outcomes in relation to ITB treatment by prospectively studying a sample of children with CP and spasticity before and after ITB implant. By doing so, we will be able to (a) examine in detail the relation between changes in spasticity and pain, (b) evaluate whether pain that persists even in the presence of reduced spasticity will be associated with poorer functional outcomes, and (c) empirically test whether treatment parameters associated with the pump implant, clinical features associated with CP, or physiological variables associated with pain, stress, and inflammation interact to influence pain specific treatment outcomes. To date, there has been no comprehensive study specific to chronic pain among children with CP treated with ITB pump implants. Considering the vulnerable clinical population for the proposed project, we believe there is an urgent imperative to try to make scientific advances from the 'bench' relevant to real-world pain and disability problems. Ultimately, the knowledge gain should transfer into a clinical decision making aide with respect to improving patient selection criteria and by informing patients, their families, and healthcare providers more completely about the full range of expected outcomes with respect to pain and function.

Scientific advances from pain research in basic models and chronic pain populations are rarely translated and applied to improve our clinical understanding of pain and disability among individuals with significant intellectual, motor, and communicative impairments associated with neurodevelopmental disorders. Despite the well document burden of chronic pain in cerebral palsy (CP), the most common cause of pediatric-onset lifelong motor and developmental disability, there is relatively little known about sensory function in relation to chronic pain. The heterogeneity in CP etiology, pathophysiology, and clinical appearance suggests new approaches may be warranted to identify measureable phenotypic patient characteristics predictive of individual variation in chronic pain outcomes. Current pain assessment approaches used in CP are limited in their ability to subgroup CP patients in relation to sensory function that may be relevant for understanding pathophysiological pain mechanisms. Most of the sensory testing research conducted with CP, while important and not in question, has relied on sensory stimuli designed to assess impaired discriminative tactile abilities such as two-point discrimination, texture and shape perception reflecting large sensory fiber afferent function. There has been little work incorporating sensory testing approaches that simultaneously evaluate loss and gain of sensory function reflecting both large and small fiber afferent integrity. The specific purpose of this application is to address the limited scientific understanding of sensory function in CP to ultimately reduce the burden of chronic pain. As a first step to close the gap between the well documented pain burden in CP and the relatively unexplored pain mechanisms in CP we are proposing to investigate an objective standardized (protocol-based) measurement approach by extending the application of a modified quantitative sensory testing (QST) protocol to characterize and compare sensory function in children with CP with and without chronic pain. Our reasoning is as follows. First, comparing sensory function between chronic pain and no chronic pain groups has the potential to reveal differences in underlying tactile/nociceptive sensory function with high relevance for improving our understanding of chronic pain in CP and other severe IDD populations. Second, applying QST to a large sample of children and adolescents with CP will provide the basis for investigating sensory function in relation to individual and clinical characteristics, and health outcomes to identify novel tailoring variables that could guide pain treatment target selection (no such guidelines exist right now). Third, using a protocol-based approach affords an important standardized context in which to investigate nociceptive and inflammatory relevant biomarkers. Finally, the logic of QST provides the basis for exploratory but highly novel tests of sensory subtype constructs (gain, loss of function) informed by the chronic/neuropathic pain research literature as a first step toward creating sensory-function based grouping of chronic pain in CP.