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Pilot Studies

Pilot #1:  Neuroimaging of Catastrophizing and Pain across States of Consciousness
PI:   Michael Smith, Ph.D.
Co-Investigators: Robert Edwards, Ph.D.

Specific Aim 1: Use fMRI and EEG to evaluate differences in the pattern of cerebral activation during the application of noxious thermal stimuli across states of consciousness (waking and NREM sleep).

Specific Aim 2: Examine the functional neuroanatomic regions mediating the influence of trait and state dimensions of catastrophizing on responses to noxious stimuli during waking and NREM Sleep.

Background and Significance: Pain is a complex phenomenon involving integrated sensory, affective, and cognitive dimensions. Neuroimaging studies suggest that pain’s neurobiologic substrates include diverse cortical and subcortical brain regions. Dysfunctions of CNS pain processing are increasingly being implicated in chronic pain disorders such as fibromyalgia (FM), a condition characterized by widespread pain and tenderness, sleep disturbance, and distress. Three neuroimaging studies have evaluated pain in FM, and each has reported enhanced responsiveness in subcortical and cortical structures associated with the sensory components of pain. However, no studies comparing pain processing in FM patients and controls have evaluated, manipulated, or controlled for cognitive aspects of pain and it remains unclear to what extent such factors play a role in the functional abnormalities observed.

Methods:  We propose to study 3 matched groups of women aged 18-55: 1) healthy controls (C, n=5), 2) patients with fibromyalgia determined be high trait catatrophizers (FM-HC, n=5), and 3) patients with fibromylagia determined to be low trait catastrophizers (FM-LC, n=5). Groups will be classified based on medical history, a standard diagnostic exam for FM, and standardized measures of trait and state catastrophizing. FM-HC and FM-LC patients will be matched for degree of pain severity and sleep quality. This project will utilize the state-of-the-art neuroimaging resources and infrastructure of the Johns Hopkins Kennedy Krieger Institute, Kirby Center for Advanced Functional Magnetic Resonance imaging.

Future Directions: Employ neuroimaging to elucidate the processes by which psychological interventions (e.g., cognitive-behavioral therapy) can systematically alter CNS processes to reduce pain and enhance quality of life.


Pilot #2:  Psychophysiologic Effects of Yoga on Rheumatoid Arthritis
PI:   Susan Bartlett, Ph.D. , Associate Professor of Medicine, Division of Rheumatology
Co-Investigators:  Joan Bathon, MD, Stephanie Haaz, MFA, CYT, Vicki Ruffing, RN

Rheumatoid arthritis (RA) is a chronic disabling and painful disease that affects more than 2 million Americans (mostly women). It is an optimal disease in which to study mind body interactions in that only weak associations have been found between disease activity and disability, pain, depression or general well being suggesting that there no simple correspondence between disease activity and important psychological and physical consequences. While there was once a fear in the medical community that exercise would increase joint inflammation, physical activity is often integrated into treatments. The American College of Rheumatology note that in addition to the general benefits of regular exercise, certain kinds of exercise have shown important benefits for people with arthritis.

A major difficulty with most exercise programs is that non adherence rates approach 70% after six months.  Because of this, interest is shifting to other movement forms such as t'ai chi, dance, and yoga,  which have been widely but anecdotally associated with improvement in health and well being.  While physical activity alone is responsible for many of the benefits, these alternative exercise approaches also include attention to focused breathing, mental engagement, stress management, social connection, and/or meditative concentration. This mind body approach may potentially make physical activity more pleasurable and therefore more beneficial physically and psychologically, and perhaps improve long term adherence rates.  To date, holistic approaches to exercise has been successfully used to treat several conditions including multiple sclerosis, heart failure, cardiovascular disease, dementia, traumatic brain injury, carpal tunnel syndrome, epilepsy, and asthma.  For persons with arthritis, the slow movements of yoga, emphasis on stretching and strength, posture, balance, and the ability to adjust the pace and intensity of movements are important components of a safe, gradual conservative exercise programming.

Yoga is an Indian approach to physical activity comprised of postures (asanas), specific breathing techniques (pranayama) and studying texts and philosophy (svadhyaya).  Currently NIH is funding several studies to evaluate the effects of yoga on management of dyspnea, insomnia, breast cancer patients receiving chemotherapy, asthma, low back pain and multiple sclerosis.  Although numerous randomized trials have evaluating the effectiveness of traditional exercise on RA and found positive outcomes, and only one trial has specifically evaluated yoga.  Dash and Telles showed in 20 patients with RA who took yoga classes, grip strength (a marker of overall strength) improved significantly in 15 days.  The goals of the proposed pilot study are to  1) develop a safe and feasible hatha yoga program for RA patients; and to evaluate the impact of this program on 2) pain, physical functioning and morning stiffness; 3) quality of life, fatigue, sleep depressive symptoms and self reported health status; and 4) selected inflammatory markers. At the conclusion of this project, we will be well positioned to prepare a competitive grant proposal to evaluate the effectiveness of yoga as adjunct therapy in RA.


Pilot #3:  The relationship of depression and hopelessness to platelet activation following acute myocardial infarction.
PI:   Roy Ziegelstein, M.D.
Co-Investigators:  D. Bush, MD, J. Fauerbach, PhD, M. Williams, MD, U. McCann, MD, Q. Hu, MD

Specific Aim 1: To determine whether depression is associated with increased platelet activation and enhanced agonist-stimulated platelet cytosolic calcium responses in the early post-myocardial infarction setting.

Specific Aim 2:  To determine whether hopelessness is associated with increased platelet activation and enhanced agonist-stimulated platelet cytosolic calcium responses in the early post-myocardial infarction setting.

Background:  Depression has been shown to predict increased morbidity and mortality among patients recovering from a myocardial infarction (MI), independent of the severity of cardiac illness. Among individuals without known coronary artery disease (CAD), depression and hopelessness each independently predict fatal ischemic heart disease  and among those with manifest CAD, hopelessness is associated with an increased mortality risk even adjusting for other "traditional" predictors of cardiac risk.  We propose that depression and hopelessness are prospectively related to mortality risk in patients with an acute MI because of an association with increased platelet activation.  Such an association, if documented, would be of great importance, since acute coronary events occur when circulating platelets are activated and then interact with complex, typically disrupted, atherosclerotic plaques. 

Methods:  Whole blood (~ 20 mL) will be obtained by venipuncture from patients admitted to the Cardiac Intensive Care Unit with acute MI who are not receiving either a glycoprotein IIb/IIIa receptor blocker or clopidogrel (patients may be receiving aspirin and/or heparin). Blood will be drawn into four 10% citrated vacutainers using a 21g butterfly needle, taking care not to activate platelets as a result of trauma. Platelet-rich plasma (PRP) will be prepared by centrifuging each sample at 1000 rpm for 9 minutes at 22 degrees C, platelet-poor plasma (PPP) will be prepared by further centrifugation at 3000 rpm for 10 minutes. Platelets will be counted with an automated counter and aggregation will be assessed after stimulation by 5 uM ADP, 5 ug/mL collagen, 10 uM epinephrine, and 1 uM serotonin.  PRP (0.4 mL) will be added to a siliconized aggregometer cuvette containing a 2 x 4 mm cylindrical aggregometer coated stir bar, and then the cuvette will be placed in the aggregometer well preheated to 37degrees C (Chronolog Model 530). PPP will be used as a blank (i.e. control).  The aggregation response will be assessed for 7 minutes.  In separate studies, platelet intracellular Ca2+ ([Ca2+]i) will be studied in platelets loaded with the Ca2+-sensitive fluorescent probe fura-2 and then immobilized on fibrinogen-coated glass coverslips in the bottom of a perfusion chamber mounted on the stage of a modified inverted fluorescence microscope.

Based on our published findings and those of others, to evaluate symptoms of depression and hopelessness, patients will be assessed using the Beck Depression Inventory (BDI) and Beck Hopelessness Scale (BHS) within the first 3 days of hospitalization for an acute MI.  Comparisons will be made on platelets obtained from patients who score in the upper quartile on the BDI (i.e. at least moderate levels of depressive symptoms) and those who score in the lowest quartile (i.e. no or mild depressive symptoms). 

Future Plans: The long-term goals of this research are to illuminate modifiable etiological factors leading to negative affect and to elucidate the psychobiological mechanisms by which negative affective states increase the risk of mortality after MI.


Pilot #4 - Title: Baltimore Health and Mental Health Study: Mood and Memory Project
PI: Hochang Benjamin Lee, M.D.

Specific Aim 1: To determine if depression occurring before the age of 50 makes people more likely to develop cognitive problems (such as problems in memory, calculation, decision-making, etc) later in life.

Background: Psuedodementia was a generally accepted concept during the 1970's-80's but has fallen out of favor. Its criteria were (1) intellectual impairment in a patient with a primary psychiatric disorder, (2) features of impairment similar to those in CNS disorders, (3) reversible cognitive deficits, and (4) no known neurological condition which accounts for smyptoms. Several studies have identified late-life depression as a risk factor for dementia, meaning that it predisposes an individual to dementia. The next question is whether the relationship between depression and dementia is casual or merely prodromal. The evidence for a temporal relationship where depression precedes dementia is convincing, but most studies are retrospective or involve short-term follow-up assessments, although the findings have been replicated. The current study is designed to investigate later life cognitive outcomes of people with depressive disorders occurring prior to the age of 50 years old. More specifically, it aims to (1) assess whether early and mid-life depressive disorders increase the risk of MCI or dementia later in life, (2) investigate the longitudinal association between early and mid-life depression and later life cognitive deficits in various neuropsychological domains, and finally (3) to estimate to what extent duration, number of episodes, and severity of early and mid-life depression predicts cognitive impairment in later life while adjusting for covariates. Within this study, the primary outcome measures are a consensus diagnosis of normal/MCI/dementia and a neuropsychological battery. The secondary outcomes are (1) to measure neurotoxicity pathway through salivary cortisol collection, and (2) to assess the vascular toxicity pathway through assessment of number of TIA, RIND, and stroke, ankle-brachial pressure, and Hachinski Ischemia score.

Methods: Participants will have an initial visit with us at a clinic, where they will receive a neurological examination and take some tests of thinking and memory. Blood pressure will be measured on the arm and ankle, and the participant will be asked to chew cotton swabs for a minute to collect saliva three times during the study. Some questions will be asked about their medical history and events in their life since they took part in the recent Baltimore ECA study. The participant will also have an informant accompanying them on their visit so that we may ask them questions about the participant's memory, behavior, and daily functioning. The results of the evaluation will be interpreted by psychologists and physicians.


Pilot #5: Depression, Cardiac Arrhythmias and Implantable Cardioverter Defibrillators (ICDs)
Dr. Joseph Marine
Co-Investigators: Dr. Gina Magyar-Russell

Specific Aim 1: To explore the relation between cardiac arrhythmias, depression, acute psychological distress, and physical and social limitations among individuals with implantable cardioverter defibrillators (ICDs).

Background: Recent research has provided preliminary evidence that states of acute mental and physical stress precede ventricular arrhythmias, yet the physiological link between psychological stress and arrhythmias, including sudden cardiac death, are unknown. Possible mechanisms include the direct effects of sympathetic nervous system arousal on arrhythmias. If ICD patients with depression have increased risk for arrhythmias, we want to determine the extent to which the increased numbers of arrhythmia events are associated with acute psychological distress. Alternatively, we are also interested in investigating how the experience of ICD therapy might contribute to acute psychological distress and the development or re-emergence of symptoms of depression.

Methods: We plan to evaluate patients who have been referred by their primary car physician or cardiologist for ICD implantation at The Johns Hopkins Bayview Medical Center. One to three weeks prior to surgical implantation of the ICD patients meet with an electrophysiologist for examination and consultation. Should they consent to ICD implantation, they will be approached about participation in the present study by a research nurse and/or research assistant. Consenting participants will be administered a series of psychological measures by the research nurse/assistant or psychology fellow. Participants will also be informed that the research staff will obtain information regarding their health care, including diagnoses, medications, medical procedures, and the number and days of hospitalization(s) from their medical records. Following ICD implantation, patients are examined by the electrophysiologist and/or his staff every 3 months for routine follow-up care. Additionally, when patients receive ICD therapies, they are instructed to contact the cardiology clinic for an appointment and interrogation of their device. Thus, follow-up assessments will occur both routinely every three months, and when ICD therapies are reported to the clinic. At all follow-up visits, patients will have their device interrogated and complete the Minnesota Living with Heart Failure Questionnaire, the Beck Anxiety Inventory, the Patient Health Questionnaire, the Functional Assessment of Chronic Illness Therapy Scale - Spiritual Well Being Scale (FACIT-Sp), and a brief (12-item) novel questionnaire concerning ICD well-being and therapy, as well as complete either 1) a one month daily diary of emotional and behavioral experiences for the month prior to their appointment, or 2) a retrospective account of their emotional and physical activities 24 hours prior to receiving the ICD therapy.


Pilot #6: Susceptibility to Neuropathic Pain Behaviors following Sciatic Inflammatory Neuritis
PI: Gayle G. Page, RN, DNSc
: Michael T. Smith, PhD and Sharon Kozachik, RN, PhD

Specific Aim 1: to develop the sciatic inflammatory neuritis (SIN) model (Chacur et al. 2001; Gazda et al. 2001) for studying factors associated with susceptibility to or resilience against the development of chronic pain.

Background:  The transition from acute to persistent pain has not been well modeled experimentally, and remains poorly understood. Although pre-clinical models of chronic neuropathic pain are very important for understanding the mechanisms of persistent neuropathic pain, there are a number of limitations in their usefulness for studying the transition from acute to persistent pain; among them are: (a) whereas substantial and direct nerve trauma is surgically initiated in most pre-clinical models, nerve trauma is not a consistent feature of human syndromes; (b) following surgically induced nerve trauma, a high proportion of animals exhibit evoked mechanical hypersensitivity, the putative feature of neuropathic pain in animals, versus a wide range of neuropathic pain incidence and characteristics following surgery in humans, 10 – 50%; and (c) whereas pre-clinical models of neuropathic pain yield relatively uniform and marked mechanical hypersensitivity quite rapidly following surgery, humans exhibit a varying course of pain development and exacerbation with phenotypic variability in important pain-related functional outcomes such as sleep and affective disturbance. Furthermore, the biologic substrates associated with these functional outcomes [e.g., sleep architecture, central sensitization, hypothalamic-pituitary-adrenal Axis (HPA) dysregulation, immune system alterations] may play a contributory role in the pathophysiologic cascade leading to persistent pain in humans. Animal studies exploring functional outcomes are sparse; therefore, the inclusion of these outcomes is necessary to establish the ecological validity of the model for extension to human pain syndromes and to identify susceptibility factors for the development of pathological intractable pain.

The sciatic inflammatory neuritis (SIN) model is proposed as a promising platform upon which to build this model as several limitations of existing models can be addressed: (a) the ability to separate the surgical intervention from the initiation of pain via zymosan; (b) the ability to vary the dosing of zymosan infused into the sciatic gelfoam wrap; (c) the capability of delivering repeated and controlled pain episodes over time in the same animal; and (d) inflammation is an aspect of virtually all neuropathic pain syndromes as initiator or consequence.

Methods:The sciatic nerve of male and female Sprague Dawley rats will be wrapped with gelfoam with an indwelling catheter system through which zymosan, yeast cell walls, can be instilled following recovery from surgery. Intermittent dosing of zymosan will be tested for variability in the development of mechanical hypersensitivity approaching 60 – 75% of animals. Mechanical sensitivity testing is undertaken using von Frey Hairs. Given that reports of the from the Watkins laboratory have shown mechanical hypersensitivity to occur ipsilateral to the SIN catheter with very low doses of zymosan, 4 – 20 ?g, and higher doses, > 40 ?g, to result in bilateral mechanical hypersensitivity, with a duration of 24 hours, our initial plan is to infuse 50 ?g zymosan at first infusion to model an acute pain insult likely to be bilateral, and infuse 2 ?g every third day thereafter. Mechanical sensitivity testing will be undertaken on day 1 before zymosan infusion and day 2, allowing the third day of each 3-day cycle to be a rest day. If this strategy results in greater than 75% of rats exhibiting pain processing alterations, the low dose will be reduced to 1 ?g. If, on the other hand, less than 60% exhibit alterations in pain processing, the dose will be increased to 3 ?g.


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