Michael Perlis - US grants

The primary aim of this project is to test the specificity of the association between abnormal levels of arousal during REM sleep and mood dysregulation in a cohort of patients with major depression and matched normal controls. Our interest in this association derives from a theoretical perspective which posits that REM sleep serves a mood regulatory function and that arousal during REM sleep may be related to a dysfunction in this system. In a preliminary study of arousal during sleep in subjects with major depression, we found that motor activity during REM sleep, as measured from the corrugator muscle, positively correlated with a measure of depressive severity that largely reflects that cognitive/affective components of depression. In the proposed investigation, we will evaluate several skeletal muscle groups in depressed and non-depressed subjects across three behavioral states (waking, NREM sleep and REM sleep) to determine the specificity of this phenomenon for depression, particular muscle groups and for REM sleep.. We will also evaluate several mood states and other measures of physiological arousal in order to determine whether the REM sleep arousal depression interaction is specific to the corrugator measure and to measures of depression as opposed to general measures of dysphoria or negative affect. Future work is proposed to evaluate the central mechanisms of REM-related arousal and their association with the development, clinical course and recurrence of depression. The proposed line of study promises to provide a functional explanation for why sleep abnormalities put the individual at risk for development of depression.

DESCRIPTION: (Adapted from applicant's abstract) It has been estimated that between 10 and 15 percent of the population has chronic Primary Insomnia. Thus, in the United States alone between 27 and 41 million people suffer from a disorder that diminishes their quality of life, negatively impacts on their work performance and puts them at increased risk for medical and psychiatric illness. The economic costs associated with insomnia are estimated to be in the tens of billions of dollars per annum. Despite its prevalence and consequences, little is known about the pathophysiology of insomnia and how it is related to the presenting symptoms of the disorder. Recent work on the spectral components of the sleep EEG show that Beta frequency EEG activity at/around sleep onset and during NREM sleep is increased in patients with Primary Insomnia, in comparison to both good sleeper controls and MDD patients with secondary insomnia. While this suggests that patients with Primary Insomnia exhibit higher than normal levels of CNS arousal at sleep onset and during NREM sleep, little is known, about whether high frequency EEG activity in insomnia is 1) limited to the Beta activity, 2) actually CNS in origin 3), if CNS in origin, preponderant at specific EEG sites, 4) varies with symptom intensity and 5) correlated with the subjective perception of sleep quality and quantity. We propose to undertake one experiment in which three groups of subjects will be studied polysomnographically for four consecutive nights. The subject groups will be 30 patients with Primary Insomnia, 30 patients with insomnia secondary to Major Depression, and 30 good sleeper controls. Digital EEG data from each night of study will be obtained from 10 sites (F3,F4,C3,C4,T5,T6,P3,P4,O1 ,02) and power spectral data will be compiled for each of the first 4 NREM and REM cycles and for each stage of sleep. Group differences for Beta-I (14-20Hz), Beta-2 (20-35Hz), Gamma (35-45Hz) and Omega (45-125 Hz) will be assessed taking into account site-to-site and night-to-night variability. In addition, we will evaluate the extent to which high frequency activity is associated with the perception of sleep quality and quantity.

DESCRIPTION (provided by applicant): It is conservatively estimated that between 40 and 70 million people are affected by chronic pain and that nearly 90% of these patients complain of poor sleep. Despite high prevalence rates, very little clinical trial work has been undertaken in patients with insomnia secondary to chronic pain. We propose a preliminary study to evaluate whether CBT for insomnia can be successfully applied to insomnia secondary to chronic pain and to further assess whether clinical gains within the sleep domain are related to greater pain tolerance, improved mood and enhanced quality of life. Subjects with insomnia secondary to pain will be recruited to participate in a parallel-groups, randomized, single blind, "placebo" controlled trial. Subjects will be assigned to one of two groups: one receiving treatment (CBT for insomnia including sleep restriction, stimulus control, cognitive therapy and sleep hygiene), the other group receiving a non-active control for measurement and therapist contact time. Treatment will occur on an individual basis by a Nurse Practitioner trained in research grade CBT for Insomnia. Sleep, pain, mood and quality of life symptoms will be monitored for a 2-week baseline period, weekly during the treatment phase and for 2-week intervals at 3 and 6 months post treatment. The data obtained from this R21 will be used to create effect size estimates for 1) the efficacy of CBT-I in patients with insomnia secondary to chronic pain and 2) the effects of improved sleep continuity on pain, mood, and quality of life. It is anticipated, both on empirical and theoretical grounds, that CBT-I will produce moderate to large effects for both the primary and secondary outcome measures. If the project is successful, these data will be used as the basis for an R01 application. It is anticipated that studies of this kind will provide the kind of evidence required to make CBT-I a standard of practice for the management of chronic pain.

DESCRIPTION (provided by applicant): Recent studies have shown that insomnia may represent a vulnerability factor for Major Depression (MDD). These findings suggest that if remitted patients with recurrent MDD received treatment for their insomnia, this intervention might prevent or delay relapse/recurrence, or at least diminish the intensity of subsequent episodes. We propose to evaluate this hypothesis by undertaking a preliminary study on the effects of Behavioral treatment for insomnia on the clinical course of patients with remitted recurrent MDD. Specifically, we propose to randomly assign 45 patients with remitted recurrent Major Depression to one of two conditions behavioral treatment for insomnia (n=30) or to a contract control monitor only group (n=15) behavior therapy was selected because this treatment modality has demonstrated efficacy with respect to insomnia yet is not likely to have direct antidepressant effects. Sleep and depression symptoms will be monitored on a weekly basis prior to treatment initiation (3-4 weeks), during active treatment (8 weeks), and for a period of up to 33 months. Monitoring will require that subjects complete daily sleep diaries, weekly Beck Depression Inventories (BDI), and monthly clinical interviews. The BDI will be used to ascertain when subjects exhibit a worsening of their depressive symptoms and will serve as a prompt for a clinical evaluation to determine whether there has been a relapse/recurrence. Weekly diaries will be used to determine 1) the acute effects of the insomnia treatment, 2) the long term efficacy of the behavioral intervention, and 3) the extent to which sleep related complaints are prodromal to new onset episodes. Monthly interviews will be used to monitor and confirm clinical state. In addition, polysomnographic (PSG) data will be acquired prior to and following treatment. These data will be used to rule out occult sleep disorders (e.g., sleep apnea and PLMs), to objectively assess severity of insomnia symptoms prior to and following treatment, and to explore, in a preliminary way, the extent to which sleep architecture variables (e.g. reduced REM latency) independently predict treatment outcome, clinical course, and/or how these measures interact with self report sleep continuity measures. It is hypothesized that behavioral treatment for insomnia in patients with remitted MDD will be associated with less depressive symptomatology during remission, longer periods of remission, less severe new onset episodes and better responses to treatment for recurrent episodes Data for each of these hypotheses will be used to calculate effect sizes and to conduct power estimates. These analyses, if they provide good feasibility data, will be used as the foundation for a R01 level application. Ultimately, If one or more of these hypotheses are borne out in the larger follow up study, this will strongly suggest that 1) CBT for insomnia may be an important strategy for the management of recurrent MDD, and 2) insomnia is not only a symptom of MDD, but also a factor in the development of the disease.

[unreadable] DESCRIPTION (provided by applicant): The lack of scientific attention devoted to the placebo effect as a phenomenon in its own right probably reflects the paucity of theoretical positions within which to organize the existing data and design new research. The proposed investigation 1) is an attempt to advance from a descriptive to an experimental analysis of the placebo effect, taking into account classical conditioning effects, and 2) examines the clinical implications of partial reinforcement as it is applied to the treatment of insomnia. Subjects with primary insomnia will be treated with zolpidem for a period of one month and then randomized to one of four groups for a period of 12 weeks: one receiving full dose zolpidem on a nightly basis (continuous reinforcement), one receiving full dose zolpidem on 14 of 28 nights where placebo is provided on non-drug nights (partial reinforcement), one receiving full dose zolpidem on 14 of 28 nights where no pills are imbibed on non-drug nights (intermittent dosing), and one receiving 5 mg dose zolpidem on a nightly basis (continuous reinforcement with half the standard dose). Following treatment, subjects will be entered into an extinction protocol during which they will 1) continue on the schedule assigned during the experimental period, 2) receive only placebo, or 3) receive neither drug nor placebo. Sleep and daily functioning will be monitored on a daily basis via sleep diaries for the duration of the study. It is hypothesized that, holding cumulative dose constant, a partial schedule of reinforcement will enable patients to better maintain their clinical gains as compared to subjects that receive either continuous reinforcement with half the standard dose or half the frequency of use. Relevance: The proposed research is not an attempt to offer a behavioral alternative to drug treatment; it is an attempt to acknowledge and capitalize on a behavioral dimension in the design of drug treatment protocols. The value of the proposed research resides in its capacity to provide for the long term treatment of insomnia in a manner that increases the durability of pharmacotherapy while reducing the overall amount of medication required. If proven effective in the current application, this new approach to pharmacotherapy and placebo effects is likely to stimulate new interdisciplinary research for the treatment of a variety of chronic diseases. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Chronic insomnia is thought to occur as a result of hyperarousal. While there is a wealth of data to support this position, there is a lack of research to define how hyperarousal interferes with sleep initiation, maintenance, and the perception of sleep quality and quantity. We propose to use Event-related Potential (ERP) techniques to evaluate information processing at sleep onset and during sleep. ERP measures of information processing have been well established in good sleepers; they have not been, however, applied to the problem of insomnia. The goal of the project is to examine the premise that the occurrence and severity of insomnia is fundamentally related to a neurobiologic preparedness to "attend to" and "identify" environmental stimuli. Following an extensive screening, patients with insomnia and good sleepers will participate in two experimental conditions, requiring that they spend four nights in the sleep laboratory over a two week period. ERP data will be gathered prior to, following, and during sleep. The ultimate objectives for this line of research are to determine 1) if insomnia is associated with a failure to inhibit information processing at sleep onset and/or during sleep, 2) if the failure to inhibit information processing at sleep onset and/or during sleep is associated with the occurrence and/or severity of insomnia symptoms, 3) what brain regions are functioning differently so as to give rise to information processing abnormalities, and 4) the extent to which pharmacologic and/or Cognitive Behavioral treatment for insomnia alters information processing abnormalities and/or the associated brain activity. Insomnia is the most prevalent sleep disorder in the general population and may be the most common of all the medical and psychiatric disorders. While considered by some to be merely an annoyance, there is a great deal of evidence that chronic insomnia is a significant risk factor for medical and psychiatric illness. Thus, it is critical to undertake research which may define "what insomnia is" (beyond the subjective experience of the disorder). This may allow for not only the development of better treatments but also for a better understanding of and "how and why" insomnia confers risk for other illnesses. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Relatively little research has been undertaken to determine what insomnia is and how insomnia may confer risk for other disease states. The lack of research may be due, in part, to the fact that the insomnia phenotype lacks objective markers, and that this is especially true for the phenomenon of cognitive arousal. This concept, while critical 1) to the patient's experience of insomnia and 2) for many etiologic theories about insomnia, is traditionally measured only by self-report. An alternative may be to use performance based measures of attentional processing. Experimental 'probe' tasks, indexing processing speed, have been used productively to explore the role of cognition in relation to wide range of psychological and habit disorders. To date, three types of task have been evaluated in patients with insomnia. These studies have successfully demonstrated the phenomenon of sleep-related attention bias, in patients with Psychophysiologic Insomnia, to semantic and pictorial stimuli. Proposed Study: The aim of the present study is to further explore the critical components of attentional processing with a view to identifying a candidate 'marker' for insomnia. In order to accomplish this, three domains of cognitive arousal will be evaluated in 4 groups. These domains are subjective mental experience (self report), performance (attentional processing) and cortical activity (qEEG). Self-report data and facial EMG will also be used to index other dimensions of arousal. The four subject groups will be Healthy Good Sleepers, patients with Psychophysiologic Insomnia and patients with Insomnia associated with Depression (acute and remitted). The primary goals will be to determine ) the extent to which the groups differ across these three cognitive domains, 2) the component processes of attention most critical to this differentiation and 3) the relative predictive utility of each of the attentional measures (viz. diagnosis).

DESCRIPTION (provided by applicant): Insomnia is common among older adults with sleep continuity disturbance being nearly three times more common in the elderly than in the overall population. This increased prevalence is of significant clinical concern as insomnia represents, in the population at large, a risk factor for new onset and recurrent psychiatric and medical illness. For older adults, the increased prevalence of insomnia may serve to make them more vulnerable to the illnesses that occur with advancing age. Despite this, very little is known about the natural history of insomnia and still less is known about the factors that appear to uniquely predispose, precipitate, and/or perpetuate insomnia in the elderly. The lack of work within this area has left the field without incidence data and temporal trends regarding new onset acute and chronic insomnia in general and in specific in older adults. Furthermore, there is no empirically based assessment of the factors that are thought to moderate/mediate maintenance of good sleep, the occurrence of (and remission/recovery from) acute insomnia, and the transition from acute to chronic insomnia. In the absence of such data, it has been hypothesized that acute insomnia occurs as an interaction between predispositional factors and acute stress (perceived or real threat) and that chronic insomnia occurs as a result of cognitive, behavioral, and conditioning factors. None of these sets of factors have ever been assessed prospectively, assessed for their relative contribution to clinical course, or assessed for how they vary with age. Accordingly, we propose to conduct a large scale, longitudinal, internet-based study across three age cohorts (middle aged [35 to 55 years], Young Elders [55 to 75 years], and Older Elders [75 years and older]). Each age cohort (comprised of 500 good sleepers and 500 individuals with acute insomnia) will be recruited via an international polling agency and surveyed on seven occasions (original Zogby survey, Intake, one, three, six, nine and 12 months) regarding life events, sleep continuity, health, mental health status, and other factors that have been theorized to mediate clinical course. In addition to the longitudinal self-report assessment, a sample of 90 subjects (over three years) with acute insomnia will be recruited from the parent sample (local to the Philadelphia region) to take part in two lab-based studies (once when the insomnia is acute and then again when the subject exhibits remission or chronic insomnia). The lab assessment will include two nights of polysomnography, the collection of urine samples at each void (to assess cortisol and melatonin levels), and the administration of an attention bias test regimen. The primary aims of the study are to: 1) profile the incidence rates of acute and chronic insomnia across the three age cohorts; 2) assess which of the theory driven factors best accounts for (alone and in combination) the various clinical course scenarios; and 3) determine if lab based biological measures distinguish between the various clinical course scenarios

PROJECT ABSTRACT/SUMMARY Prospective data on the sleep of women as they transition from pre-pregnancy through pregnancy and to postpartum are needed to predict maternal and infant health outcomes. Sleep disturbance among new mothers is ubiquitous and presents a profound challenge, not only to mothers' health and well-being, but also to that of their infant. While some sleep disruptions may be normative and resolve with childbirth and the adaptation to new motherhood, others may be maladaptive and confer risk for adverse pregnancy and/or poor maternal or infant health outcomes. For example, sleep disturbance, globally measured, has been associated with antenatal depression, preterm birth, longer labors, more C-section deliveries, and postpartum depression. Which sleep disorders specifically confer risk is only now being delineated. Longitudinal studies are needed to determine when, for whom, and under what conditions, sleep disturbance gives rise to pathology. Prospective studies of this nature, however, have been limited, due to challenges in recruiting large, representative samples, maintaining enrolled participants, and ensuring timely completion of study instruments. In keeping with the R21 mechanism, the present study is designed to 1) pilot the feasibility of a novel methodological approach (recruitment via a national polling agency and registry, the use of an online questionnaire system, the provision of regular feedback via email and a study website, and a lottery-based incentive system) aimed to systematically and efficiently cull longitudinal data of this kind; 2) evaluate pregnant and non-pregnant women for differences with respect to cumulative sleep disorder morbidity, and determine which specific sleep disorders account for these differences; and 3) gather pilot data on the association between sleep disturbance and maternal-infant outcomes. Nulliparous women who do not intend to conceive in the next 18 months, who intend to conceive in the next 18 months, and who are currently in their first trimester, will be recruited to participate in a 16-18 month study. Feasibility will be assessed by evaluating recruitment, retention, and compliance rates and whether these meet pre-specified threshold criteria. Both sleep continuity and sleep disorder symptoms will be systematically tracked in relation to maternal and infant outcomes (e.g., fatigue, sleepiness, mood disturbance, gestational diabetes, incidence of pregnancy loss, incidence of pre-term birth, and birth weight). Given data to support the feasibility of these strategies, the methodological package proposed can be applied to numerous longitudinal designs, including, and apart from, the proposed study. Finally, the content of the proposed study will serve to allow an estimation of the overall association between sleep disturbance and maternal and infant health (i.e., an overall association between the two sets of measures) and for the evaluation of specific associations (e.g., OSA-related symptoms and gestational diabetes). Ultimately, if successful, this program of research may help define when sleep disorder interventions are needed to promote both maternal health and good infant outcomes.

? DESCRIPTION (provided by applicant): Insomnia is nearly twice as common among older adults as it is in the general population. This is of significant clinical concern as insomnia is a risk factor for new onset and recurrent psychiatric and medical illness. Taken together, the prevalence and consequences of insomnia in older adults suggests that insomnia should not go untreated. This potential clinical imperative is further underscored by 1) the reconceptualization of Insomnia within the DSM-5 and ICSD-3 as a disorder (vs. a symptom of other disorders) and 2) the findings that targeted treatment of sleep continuity disturbance may produce clinical gains for medical and psychiatric disorders that occur comorbidly with insomnia. Thus, at present, the question is not whether to treat but how to best treat the disorder in general, and specifically in the context of older adults. Of the available medical treatments, the best studied strategies are benzodiazepines and benzodiazepine receptor agonists (BZRAs). In both cases, treatment is typically accomplished with either nightly or intermittent dosing. In the case of nightly dosing (QHS), BZRAs have been found to be safe and efficacious for periods of up to a year. Less clear is whether such efficacy can be maintained over the course of years or decades. In the case of intermittent dosing (IDS), the reduced usage strategy is thought to extend the efficacy and safety half-life of pharmacotherapy, but at a cost: little or no clinical effects on non-medication nights. In order to address this issue, we propose to evaluate an alternative approach that is based on the behavioral principles of conditioning and reinforcement. Specifically, we propose to garner treatment responses with full dose treatment (1 month) and then conduct maintenance therapy using intermittent dosing with placebos on non-medication nights. This approach, by expectancy alone, should provide for better clinical outcomes than standard intermittent dosing. What makes the study theoretically interesting is the underlying concept: that the initial treatment response allows for the medication vehicle (the capsule) to become a conditioned stimulus for the therapeutic response (sleepiness and sleep) and that this can be maintained over time (if not indefinitely) with partial reinforcement. Building upon the findings from our prior investigation with partial reinforcement, we propose to assess two low frequency approaches to maintenance therapy in a three phase study. In Phase 1, all subjects receive zolpidem nightly for one month and are assessed for treatment response. In Phase 2, responders are randomized to one of four maintenance conditions for three months: Nightly medication use (QHS); one of two low frequency partial reinforcement conditions (1 or 3 active doses per week with placebos on non-medication nights); and a low frequency IDS condition (1 to 3 active doses per week, without placebos). Phase 3 will be an extension period to assess, over 9 months, the long-term durability of the approaches. The outcomes for the study will be: rate of relapse, latency to relapse, average sleep continuity, and number and severity of medical symptoms during treatment. The primary hypothesis for the study is that the partial reinforcement conditions will produce similar outcomes to nightly dosing and superior outcomes to the IDS condition.

BEHAVIORAL SLEEP MEDICINE: TRAINING IN SLEEP & AGING ABSTRACT Goals: In this proposal, Dr. Michael Perlis requests support to: 1) stabilize and expand his mentoring of junior investigators in the domain of behavioral sleep medicine and in the biopsychosocial approach to the study of insomnia (etiology, pathophysiology, treatment outcome research, and treatment mechanisms of action studies); 2) engage a program of educational activities that will provide him and his mentees with a strong foundation for the assessment of aging as a moderating factor for insomnia research; and 3) establish a collaborative network with junior investigators to conduct hypothesis-driven research with his NIA supported project on the natural history of insomnia. Background: Dr. Perlis has been involved in patient-oriented research since his mid-20's. He has been the beneficiary of exceptional mentorship and has carried forward this tradition over the entirety of his career. His research on Insomnia Disorder extends from basic research to patient-oriented research. Qualifications: The candidate has extensive experience as a PI, Co-PI, or Co-I on multiple NIH awards and a successful track record in mentoring others via NIH K23 and R21 mechanisms. Environment: The University of Pennsylvania (Penn) is one of the premier centers for sleep and chronobiology research and clinical work. As such, it has much to offer both the PI and his trainees. Development Activities: The core activity for the mentor's professional development will be the implementation of a monthly seminar series focused on Sleep and Aging. Leading scientists will be invited to Penn to discuss their ideas with respect to the effects of aging on sleep need, sleep ability and sleep opportunity and how alterations within these domains confer increased risk for sleep disorders and adverse health outcomes. In addition, the mentor/PI will take one workshop or course per year focused on biopsychosocial perspectives on aging and one workshop pertaining to bioethics. Mentoring Program: As the Director of Penn's Behavioral Sleep Medicine program, Dr. Perlis has created a unique set of educational activities that attract a wide array of trainees including established professionals, junior investigators, post-doctoral fellows, graduate and medical students, post baccalaureates, and undergraduates. The plan for this K24 is to provide trainees with a set of educational activities that include professional development, focused training in behavioral sleep medicine, and an in-depth appreciation regarding the quantitative assessment of sleep continuity (e.g., sleep diary assessments, actigraphy, PSG, & QEEG). Research: The candidate proposes to create a collaborative network to conduct archival analysis with Jr. Investigators using his NIA supported natural history of insomnia databases (R01AG041783). The individuals invited will have specialty areas apart from the PI, and thus will serve as an opportunity for the PI to both teach and learn. A conference will be held in the 3rd year of the award at which the collaborators will present and discuss their data as a group. Significance: This K24 will support Dr. Perlis in his efforts to provide patient-oriented research training to the next generation.