Sigrid Veasey

University of Pennsylvania | UP · Perelman School of Medicine

Disrupted sleep is a symptom of many psychiatric disorders, including substance use disorders. Most drugs of abuse, including opioids, disrupt sleep. However, the extent and consequence of opioid-induced sleep disturbance, especially during chronic drug exposure, is understudied. We have previously shown that sleep disturbance alters voluntary morp...

Chronic sleep disruption is a risk factor for Alzheimer’s disease (AD), yet mechanisms by which sleep disturbances might promote or exacerbate AD are not understood. Short-term sleep loss acutely increases hippocampal amyloid β (Aβ) in wild type (WT) mice and long-term sleep loss increases amyloid plaque in AD transgenic mouse models. Both effects...

Intermittent fluctuation in oxyhemoglobin saturation in sleep is a hallmark feature of obstructive sleep apnea (OSA). Initially, because the desaturation events are so brief, there was a general belief that the events were of little consequence. Studies in animal models have highlighted the effects of brief episodic fluctuation in oxygen on neurona...

Recent studies in both humans and animal models call into question the completeness of recovery after chronic sleep disruption. Studies in humans have identified cognitive domains particularly vulnerable to delayed or incomplete recovery after chronic sleep disruption, including sustained vigilance and episodic memory. These findings, in turn, prov...

Introduction Sleep deprivation impairs hippocampal-dependent memory, and hippocampal-dependent memory impairments occur in some dementias, including Alzheimer’s disease. As our population continues to age, understanding the molecular basis for memory impairments is increasingly important. We hypothesized that early life sleep fragmentation would re...

Introduction Chronic sleep disruption (CSD) in young adult mice leads to phenotypes consistent with early (pre-plaque) Alzheimer’s Disease (AD), including increased Aβ and hippocampal neuron loss. Mechanisms underlying this injury are not known. Both acute sleep loss and AD activate cofilin, a regulator of actin dynamics. Activated cofilin (AC) in...

Introduction Fragmented sleep occurs when there are repetitive, short interruptions of sleep, resulting in less than six hours of sleep per day. Overall, however, in the United States, sleep fragmentation is reported by 30% of employed adults. Sleep fragmentation may be a risk factor for Alzheimer's disease, and orexin reduction appears effective i...

The opioid epidemic remains a significant healthcare problem and is attributable to over 100,000 deaths per year. Poor sleep increases sensitivity to pain, impulsivity, inattention, and negative affect, all of which might perpetuate drug use. Opioid users have disrupted sleep during drug use and withdrawal and report poor sleep as a reason for rela...

Chronic short sleep (CSS) is prevalent in modern societies and has been proposed as a risk factor for Alzheimer’s disease (AD). In support, short-term sleep loss acutely increases levels of amyloid β (Aβ) and tau in wild type (WT) mice and humans, and sleep disturbances predict cognitive decline in older adults. We have shown that CSS induces injur...

Sleep fragmentation is defined qualitatively by an increased frequency arousals across the sleep period. This condition is present in many sleep disorders, including sleep apnea. Yet, we are only now beginning to understand the significance of sleep fragmentation in brain and body health. A summary of findings from human and animal models are provi...

Millions of Americans suffer from opiate use disorder, and over 100 die every day from opioid overdoses. Opioid use often progresses into a vicious cycle of abuse and withdrawal, resulting in very high rates of relapse. Although the physical and psychologic symptoms of opiate withdrawal are well-documented, sleep disturbances caused by chronic opio...

Chronic short sleep or extended wake periods are commonly observed in most industrialized countries. Previously neurobehavioral impairment following sleep loss was considered to be a readily reversible occurrence, normalized upon recovery sleep. Recent clinical studies suggest that chronic short sleep and sleep disruption may be risk factors for ne...

Introduction Chronic short sleep is prevalent in society and evidence is accumulating for the role of sleep loss in neurodegenerative processes, including Alzheimer’s disease (AD). Sleep loss can accelerate AD pathology in transgenic animals that overexpress either Abeta42 or tau. However, it is not known whether sleep loss can initiate AD like pat...

Obstructive sleep apnea is common and is associated with daytime sleepiness and increased risks of motor vehicle accidents and cardiovascular disease. CPAP is considered first-line therapy for symptomatic or moderate-to-severe obstructive sleep apnea; mandibular-advancement devices and various surgical options are other approaches.

Brainstem locus ceruleus neurons (LCn) are among the first neurons across the lifespan to evidence tau pathology, and LCn are implicated in tau propagation throughout the cortices. Yet, events influencing LCn tau are poorly understood. Activated persistently across wakefulness, LCn experience significant metabolic stress in response to chronic shor...

Background and aims Associated with numerous metabolic and behavioral abnormalities, obesity is classified by metrics reliant on body weight (such as body mass index). However, overnutrition is the common cause of obesity, and may independently contribute to these obesity-related abnormalities. Here, we use dietary challenges to parse apart the rel...

RNA-seq results of remaining DEGs discovered by any RNA-seq analysis approach (see Table 1). Note the low expression counts for izfk3, tk1, and cldn2. Ikfz3: IKAROS family zinc finger 3; tk1: thymidine kinase 1; cldn2: claudin 2; atxn7l2: ataxin 7 like 2; rbm3: RNA-binding protein 3; c4b: complement 4b. **p<0.01, ***p<0.001 comparing two DS conditi...

Gene set enrichment analysis (GSEA) results. Using the ‘High Filter’ data set of RNA-seq results (see Methods), GSEA reveals significantly enriched pathways in HFD → RC animals compared to RC → HFD. Using both raw and log2-transformed data, we found the same six enriched pathways at an FWER < 0.05. FDR: False discovery rate; FWER: Family wise error...

Gene name, NCBI reference sequence, and catalog number of Taqman primer/probes used for RT-qPCR experiments. (DOCX)

Activity-based estimates for sleep/wake behavior are unreliable for DIO mice. Obese mice sleep ~1–2 hours more per day and exhibit increased sleep/wake fragmentation compared to lean animals [23]. Fig 2A shows that DIO mice are hypoactive compared to lean mice during the dark period, when these sleep effects are most pronounced. An activity-based a...

RT-qPCR validation of RNA-seq results including neuropeptide genes for which differential expression was not expected. (Top row) Normalized read counts from RNA-seq analysis. (Middle row) RT-qPCR validation using tissue used for RNA-seq. (Bottom row) RT-qPCR validation using independent tissue samples not used for RNA-seq. (A-C) Sbno2 and (D-F) ser...

Thyroid hormone measurements. (A) Thyroid-stimulating hormone (TSH) showed highly variable expression levels across samples, contributing to non-significant group effects (p = 0.9658). (B) Thyroxine (T4) levels were not robustly different between dietary conditions. Triiodothyronine (T3) levels were also measured, but most samples were below detect...

Linear regression analysis for caloric intake and locomotor activity. (A) Caloric intake is not related to body weight. (B) Energy intake is positively related to acute weight changes (Δbody weight). (C) Activity patterns are negatively associated with body weight. (D) Locomotor activity is not related to Δbody weight. (TIF)

RNA-seq total read counts and contamination from ribosomal RNA and mitochondrial DNA. (DOCX)

Details statistical results reporting adjusted p-values. Only comparisons that reached overall significance (ANOVA: p<0.05) are shown. (DOCX)

Body weight and Δbody weight are not correlated across all dietary conditions. Scatter plot of absolute body weight (Post-DS, in grams) vs Δbody weight (percent change in body weight from Pre- to Post-DS). There is no correlation between body weight and Δbody weight for these mice across all groups (R2 = 8.8x10-5, p = 0.94). RC NoDS, n = 16; RC → H...

Immunofluorescence localization of the VH. One mouse was deeply anesthetized and transcardially perfused with ice-cold 4% paraformaldehyde (pH = 7.5). The brain was left in 4% PF overnight, and then switched to 30% sucrose the following day. A cryostat was used to coronally section the brain (50 μm) and free-floating sections were placed into block...

Introduction Brainstem locus coeruleus neurons (LCn) are among the first neurons across the lifespan to evidence tau pathology, and LCn are implicated in tau propagation throughout the cortices. Yet, events influencing LCn tau are poorly understood. Activated persistently across wakefulness, LCn experience significant metabolic stress in response t...

Introduction Chronic short sleep (CSS), common in modern society, results in degeneration of Locus Coeruleus neuron (LCn). Recently we have identified increased concentrations of phosphorylated microtubule associated protein tau (p-tau). P-tau is implicated in degeneration of neurons in several conditions including Alzheimer’s and Epilepsy. Here, w...

This review details tumor necrosis factor alpha (TNF) biology and its role in sleep, and describes how TNF medications influence sleep/wake activity. Substantial evidence from healthy young animals indicates acute enhancement or inhibition of endogenous brain TNF respectively promotes and inhibits sleep. In contrast, the role of TNF in sleep in mos...

Approximately one-third of adolescents and adults in developed countries regularly experience insufficient sleep across the school and/or work week interspersed with weekend catch up sleep. This common practice of weekend recovery sleep reduces subjective sleepiness, yet recent studies demonstrate that one weekend of recovery sleep may not be suffi...

Introduction Sleep loss, highly prevalent in modern societies, can increase extracellular cortical amyloid; yet whether insufficient sleep can influence the temporal progression or development of spontaneous Alzheimer’s disease is not known. Locus coeruleus neurons (LCn) are activated persistently across waking and are an early site for pathogenic...

Mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT), a neurological disorder affecting cognitive development, respiration, and motor function. Genetic restoration of MeCP2 expression reverses RTT-like phenotypes in mice, highlighting the need to search for therapeutic approaches. Here, we have deve...

Study objectives: Intermittent short sleep (ISS) is pervasive among students and workers in modern societies, yet the lasting consequences of repeated short sleep on behavior and brain health are largely unexplored. Wake-activated neurons may be at increased risk of metabolic injury across sustained wakefulness. Methods: To examine the effects o...

Excessive daytime sleepiness commonly affects obese people, even in those without sleep apnea, yet its causes remain uncertain. We sought to determine whether acute dietary changes could induce or rescue wake impairments independent of body weight. We implemented a novel feeding paradigm that generates two groups of mice with equal body weight but...

Chronic sleep disruption (CSD) is a cardinal feature of sleep apnea that predicts impaired wakefulness. Despite effective treatment of apneas and sleep disruption, patients with sleep apnea may have persistent somnolence. Lasting wake disturbances in treated sleep apnea raise the possibility that CSD may induce sufficient degeneration in wake-activ...

Conventional T (Tcon) cells and Foxp3(+) T-regulatory (Treg) cells are thought to have differing metabolic requirements, but little is known of mitochondrial functions within these cell populations in vivo. In murine studies, we found that activation of both Tcon and Treg cells led to myocyte enhancer factor 2 (Mef2)-induced expression of genes imp...

Modern society enables a shortening of sleep times, yet long-term consequences of extended wakefulness on the brain are largely unknown. Essential for optimal alertness, locus ceruleus neurons (LCns) are metabolically active neurons that fire at increased rates across sustained wakefulness. We hypothesized that wakefulness is a metabolic stressor t...

Study objectives: Delayed hypercapnic arousals may occur in obstructive sleep apnea. The impaired arousal response is expected to promote more pronounced oxyhemoglobin desaturations. We hypothesized that long-term sleep fragmentation (SF) results in injury to or dysfunction of wake-active neurons that manifests, in part, as a delayed hypercapnic a...

The invention relates to compositions and methods for treating Obstructive Sleep Apnea (OSA). Specifically, the invention relates to the use of NADPH Oxigenase inhibitors in compositions and methods for treating OSA in a subject.

Exposure to the variable oxygenation patterns in obstructive sleep apnea (OSA) causes oxidative stress within the brain. We hypothesized that this stress is associated with increased levels of redox-active metals and white matter injury. Participants were randomly allocated to a control or experimental group (single independent variable). Universit...

Extracellular pH (pHe) and intracellular pH (pHi) are important factors for the excitability of chemosensitive central respiratory neurons that play an important role in respiration and obstructive sleep apnea. It has been proposed that inhibition of central Na+/ H+ exchanger 3 (NHE-3), a key pHi regulator in the brainstem, decreases the pHi, leadi...

Obstructive sleep apnea (OSA) is associated with cognitive impairment and neuronal injury. Long-term exposure to intermittent hypoxia (LTIH) in rodents, modeling the oxygenation patterns in sleep apnea, results in NADPH oxidase 2 (Nox2) oxidative injury to many neuronal populations. Brainstem motoneurons susceptible to LTIH injury show uncompensate...

Obstructive sleep apnea is increasingly recognized as an important contributor to cognitive impairment, metabolic derangements, and cardiovascular disease and mortality. Identifying the mechanisms by which this prevalent disorder influences health outcomes is now of utmost importance. As the prevalence of this disorder steadily increases, therapies...

Background: Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the vent...

Obstructive sleep apnea (OSA) is a highly prevalent condition that is associated with significant neurobehavioral impairments. Cognitive abnormalities identified in individuals with OSA include impaired verbal memory, planning, reasoning, vigilance, and mood. Therapy for OSA improves some but not all neurobehavioral outcomes, supporting a direct ro...

Increasing numbers of overweight children and adults are presenting to sleep medicine clinics for evaluation and treatment of sleepiness. Sleepiness negatively affects quality of life, mental health, productivity, and safety. Thus, it is essential to comprehensively address all potential causes of sleepiness. While many obese individuals presenting...

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder associated with substantial cardiovascular and neurobehavioral morbidity. Yet this is a disorder for which there are no widely effective pharmacotherapies. The pathophysiology of obstructive sleep apnea namely, normal respiration in waking with disordered breathing only in sl...

Significant advancements have been made over the past three decades to better understand the disease entity of obstructive sleep apnea and the mechanisms by which this prevalent disorder imparts injury. Once considered a disorder of reversible sleepiness and insignificant arterial oxygen desaturations because of their intermittency, obstructive sle...

Pulmonary arterial vascular smooth muscle (PAVSM) cell proliferation is a key pathophysiological component of vascular remodeling in pulmonary arterial hypertension (PAH) for which cellular and molecular mechanisms are poorly understood. The goal of our study was to determine the role of mammalian target of rapamycin (mTOR) in PAVSM cell proliferat...

Fragmentation of wakefulness and sleep are expected outcomes of advanced aging. We hypothesize that wake neurons develop endoplasmic reticulum dyshomeostasis with aging, in parallel with impaired wakefulness. In this series of experiments, we sought to more fully characterize age-related changes in wakefulness and then, in relevant wake neuronal po...

Wake neurons in the basal forebrain and brainstem provide critical inputs to optimize alertness and attention. These neurons, however, evidence heightened vulnerability to a diverse array of metabolic challenges, including aging. SIRT1 is an nicotinamide adenine dinucleotide responsive deacetylase serving diverse adaptive responses to metabolic cha...

Previous studies have found an association between obstructive sleep apnea (OSA) and chronic kidney disease (CKD). However, subjects with confounding factors such as diabetes and hypertension were not excluded. The purpose of the present study was to determine whether patients with OSA without meeting criteria for diabetes or hypertension would als...

Obstructive sleep apnoea (OSA) is a prevalent disorder with significant co-morbidities. Presently only rarely, treatments for obstructive sleep apnoea are curative. More typically, this is a disease that requires lifelong intervention and commitment from both the patients and healthcare providers. In light of the commitments, there is no uniform ap...

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to co...

Sleep-disordered breathing encapsulates a diverse collection of sleep apnea syndromes. Of these syndromes, symptomatic obstructive sleep apnea is the most prevalent, present in 5% of adults and 1% of children in developed countries. Obstructive sleep apnea is an independent risk factor for diabetes, hypertension, myocardial infarction, and stroke....

Sleepiness has long been recognized as a presenting symptom in obstructive sleep apnea syndrome, but persistent neurocognitive injury from sleep apnea has been appreciated only recently. Although therapy for sleep apnea markedly improves daytime symptoms, cognitive impairments may persist despite long-term therapy with continuous positive airway pr...

Obstructive sleep apnea (OSA) afflicts tens of millions of Americans and hundreds of millions of people worldwide, and the possibility that the disease may cause permanent neural injury is therefore a significant concern. Numerous comorbidities--including diabetes, cardiovascular disease, and obesity--are associated with the disease, and it is quit...

Edited by Sigrid Veasey, M.D. Center for Sleep and Respiratory Neurobiology Department of Medicine University of Pennsylvania Oxidative changes are observed in healthy aging of the nervous system, neurodegenerative processes and other forms of neural injury. At the same time, reactive oxygen species and reactive nitrogen species play critical roles...

In November 2007, the first Certification Examination in Sleep Medicine was administered to 1,882 candidates under the cosponsorship of five member boards of the American Board of Medical Specialties (ABMS)--the American Board of Internal Medicine, the American Board of Family Medicine, the American Board of Otolaryngology, the American Board of Pe...

n/a Key words: neuropeptide y, substance p, hypoxia.

Obstructive sleep apnea is associated with neural injury and dysfunction. Hypoxia/reoxygenation exposures, modeling sleep apnea, injure select populations of neurons, including hypoglossal motoneurons. The mechanisms underlying this motoneuron injury are not understood. We hypothesize that endoplasmic reticulum injury contributes to motoneuron demi...

The neural mechanisms through which the state of anesthesia arises and dissipates remain unknown. One common belief is that emergence from anesthesia is the inverse process of induction, brought about by elimination of anesthetic drugs from their CNS site(s) of action. Anesthetic-induced unconsciousness may result from specific interactions of anes...

Obstructive sleep apnea syndrome is a highly prevalent disorder, associated with numerous cardiovascular and neurobehavioral morbidities. A unique feature of this syndrome is the sleep-state dependency of upper airway collapse and obstruction. Indeed, individuals with obstructive sleep apnea have normal breathing while awake and only manifest airwa...

Current treatment approaches to the problem of obstructive sleep apnoea (OSA) have limitations. Specifically, invasive anatomical-based surgery and dental appliances typically do not alleviate obstruction at an acceptable rate, and compliance to continuous positive airway pressure (CPAP) devices is frequently suboptimal. Neurotoxinological treatmen...

The presence of refractory wake impairments in many individuals with severe sleep apnea led us to hypothesize that the hypoxia/reoxygenation events in sleep apnea permanently damage wake-active neurons. We now confirm that long-term exposure to hypoxia/reoxygenation in adult mice results in irreversible wake impairments. Functionality and injury we...

severe obstructive sleep apnea fires a complex array of physiological stressors rapidly and relentlessly across each period of sleep. With each occlusion of the upper airway, particularly in obese individuals, arterial oxygen content and delivery fall precipitously, carbon dioxide rises, acidosis

A significant number of patients with obstructive sleep apnea neither tolerate positive airway pressure (PAP) therapy nor achieve successful outcomes from either upper airway surgeries or use of an oral appliance. The purpose of this paper, therefore, was to systematically evaluate available peer-reviewed data on the effectiveness of adjunctive med...

Adult male mice exposed to long-term intermittent hypoxia (LTIH), modeling sleep apnea oxygenation patterns, develop nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent residual hypersomnolence and oxidative injury in select brain regions, including wake-active regions. Premenopausal females are less susceptible to selective oxida...

A growing body of work supports the concept that menopause is a risk factor for obstructive sleep apnea (OSA). These observations come from clinical and population data examining the relationship between menopausal status and sleep-disordered breathing (SDB), studies examining the clinical characteristics of disease in preand postmenopausal women,...

Impaired rapid eye movement sleep (REMS) is commonly observed in Alzheimer's disease, suggesting injury to mesopontine cholinergic neurons. We sought to determine whether abnormal beta-amyloid peptides impair REMS and injure mesopontine cholinergic neurons in transgenic (hAPP695.SWE) mice (Tg2576) that model brain amyloid pathologies. Tg2576 mice a...