Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation: A Report From the National Heart, Lung, and Blood Institute and the National Institutes of Health Office of the Director Workshop

doi:10.1016/j.jacbts.2021.11.003

Review

. 2022 Jan 26;7(3):265-293.

doi: 10.1016/j.jacbts.2021.11.003. eCollection 2022 Mar.

Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation: A Report From the National Heart, Lung, and Blood Institute and the National Institutes of Health Office of the Director Workshop

Reena Mehra^{1

2}, Olga A Tjurmina³, Olujimi A Ajijola⁴, Rishi Arora⁵, Donald C Bolser⁶, Mark W Chapleau⁷, Peng-Sheng Chen⁸, Colleen E Clancy⁹, Brian P Delisle¹⁰, Michael R Gold¹¹, Jeffrey J Goldberger¹², David S Goldstein¹³, Beth A Habecker¹⁴, M Louis Handoko¹⁵, Robert Harvey¹⁶, James P Hummel¹⁷, Thomas Hund¹⁸, Christian Meyer¹⁹, Susan Redline²⁰, Crystal M Ripplinger²¹, Marc A Simon^{22

23}, Virend K Somers²⁴, Stavros Stavrakis²⁵, Thomas Taylor-Clark²⁶, Bradley Joel Undem²⁷, Richard L Verrier²⁸, Irving H Zucker²⁹, George Sopko³, Kalyanam Shivkumar⁴

Affiliations

¹ Cleveland Clinic, Cleveland, Ohio, USA.
² Case Western Reserve University, Cleveland, Ohio, USA.
³ National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
⁴ David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁵ Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA.
⁶ University of Florida, Gainesville, Florida, USA.
⁷ University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
⁸ Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁹ University of California Davis, Davis, California, USA.
¹⁰ University of Kentucky, Lexington, Kentucky, USA.
¹¹ Medical University of South Carolina, Charleston, South Carolina, USA.
¹² University of Miami Miller School of Medicine, Miami, Florida, USA.
¹³ National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹⁴ Oregon Health and Science University School of Medicine, Portland, Oregon, USA.
¹⁵ Amsterdam University Medical Centers, Amsterdam, the Netherlands.
¹⁶ University of Nevada Reno, Reno, Nevada, USA.
¹⁷ Yale University School of Medicine, New Haven, Connecticut, USA.
¹⁸ Ohio State University, Columbus, Ohio, USA.
¹⁹ University of Düsseldorf, Germany, Düsseldorf, Germany.
²⁰ Harvard Medical School, Boston, Massachusetts, USA.
²¹ University of California Davis School of Medicine, Davis, California, USA.
²² University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
²³ University of California-San Francisco, San Francisco, California, USA.
²⁴ Mayo Clinic, Rochester, Minnesota, USA.
²⁵ University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
²⁶ University of South Florida, Tampa, Florida, USA.
²⁷ Johns Hopkins University, Baltimore, Maryland, USA.
²⁸ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
²⁹ University of Nebraska Medical Center, Omaha, Nebraska, USA.

PMID: 35411324
PMCID: PMC8993767
DOI: 10.1016/j.jacbts.2021.11.003

Review

Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation: A Report From the National Heart, Lung, and Blood Institute and the National Institutes of Health Office of the Director Workshop

Reena Mehra et al. JACC Basic Transl Sci. 2022.

. 2022 Jan 26;7(3):265-293.

doi: 10.1016/j.jacbts.2021.11.003. eCollection 2022 Mar.

Authors

Affiliations

¹ Cleveland Clinic, Cleveland, Ohio, USA.
² Case Western Reserve University, Cleveland, Ohio, USA.
³ National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
⁴ David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁵ Feinberg School of Medicine at Northwestern University, Chicago, Illinois, USA.
⁶ University of Florida, Gainesville, Florida, USA.
⁷ University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
⁸ Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁹ University of California Davis, Davis, California, USA.
¹⁰ University of Kentucky, Lexington, Kentucky, USA.
¹¹ Medical University of South Carolina, Charleston, South Carolina, USA.
¹² University of Miami Miller School of Medicine, Miami, Florida, USA.
¹³ National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
¹⁴ Oregon Health and Science University School of Medicine, Portland, Oregon, USA.
¹⁵ Amsterdam University Medical Centers, Amsterdam, the Netherlands.
¹⁶ University of Nevada Reno, Reno, Nevada, USA.
¹⁷ Yale University School of Medicine, New Haven, Connecticut, USA.
¹⁸ Ohio State University, Columbus, Ohio, USA.
¹⁹ University of Düsseldorf, Germany, Düsseldorf, Germany.
²⁰ Harvard Medical School, Boston, Massachusetts, USA.
²¹ University of California Davis School of Medicine, Davis, California, USA.
²² University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
²³ University of California-San Francisco, San Francisco, California, USA.
²⁴ Mayo Clinic, Rochester, Minnesota, USA.
²⁵ University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
²⁶ University of South Florida, Tampa, Florida, USA.
²⁷ Johns Hopkins University, Baltimore, Maryland, USA.
²⁸ Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
²⁹ University of Nebraska Medical Center, Omaha, Nebraska, USA.

PMID: 35411324
PMCID: PMC8993767
DOI: 10.1016/j.jacbts.2021.11.003

Abstract

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed.

Keywords: ACE, angiotensin-converting enzyme; AD, autonomic dysregulation; AF, atrial fibrillation; ANS, autonomic nervous system; Ach, acetylcholine; CNS, central nervous system; COPD, chronic obstructive pulmonary disease; CSA, central sleep apnea; CVD, cardiovascular disease; ECG, electrocardiogram; EV, extracellular vesicle; GP, ganglionated plexi; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HRV, heart rate variability; LQT, long QT; MI, myocardial infarction; NE, norepinephrine; NHLBI, National Heart, Lung, and Blood Institute; NPY, neuropeptide Y; NREM, non-rapid eye movement; OSA, obstructive sleep apnea; PAH, pulmonary arterial hypertension; PV, pulmonary vein; REM, rapid eye movement; RV, right ventricular; SCD, sudden cardiac death; SDB, sleep disordered breathing; SNA, sympathetic nerve activity; SNSA, sympathetic nervous system activity; TLD, targeted lung denervation; asthma; atrial fibrillation; autonomic nervous system; cardiopulmonary; chronic obstructive pulmonary disease; circadian; heart failure; pulmonary arterial hypertension; sleep apnea; ventricular arrhythmia.

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Conflict of interest statement

This workshop was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institutes of Health (NIH) Office of the Director. Dr Ajijola is supported by NIH grants DP2 OD024323, OT2 OD028201, and OT2 OD023848, Dr Chen was supported by NIH grants OT2 OD028190, R01 HL139829, and the Burns & Allen Chair in Cardiology Research, Cedars-Sinai Medical Center. Dr Clancy has received research funding from NIH grants OT2 OD026580, OT2 OD026580, R01 HL152681, R01 HL128170, and U01 HL126273, InCarda Therapeutics, and the Department of Physiology and Membrane Biology Research Partnership Fund, Oracle cloud for research allocation. Dr Delisle is supported by NIH grants R01 HL153042, R01 HL141343, and the American Heart Association grant 20IPA35320141. Dr Habecker was supported by NIH grants R01 HL093056 and R01 HL146822. Dr Handoko has received an educational grant from Novartis and Boehringer Ingelheim. Dr Redline has received research funding from NIH grants R35 HL135818, R01 HL133684, U10 HD036801, R01 HL137234, R01 DK118736, R01 AG056331, and U24 HL140412, and Jazz Pharmaceuticals. Dr Ripplinger is supported in part by research funding from NIH grants OT2 OD026580, R01 HL093056, and R01 HL111600. Dr Somers is supported by NIH grants R01 HL065176 and R01 HL134885. Dr Stavrakis was supported by NIH grant R21 AG057879. Dr Taylor-Clark is supported by NIH grants R01 HL152219, U01 NS113868, OT2 OD023854, R21 DK124894, R01 DK110366, and U01 DK110366. Dr Undem is supported by NIH grant R35 HL155671. Dr Zucker has received support from Sorrento Therapeutics, Inc. and from NIH grant R01 HL126796. Dr Shivkumar is supported by NIH grants OT2 OD028201 and OT2 OD023848. Dr Ajijola is a cofounder and equity holder of NeuCures; has served as a consultant for Merck and Biosense-Webster Inc. Dr Gold has received clinical trial research funding from Boston Scientific and Medtronic; and has been a consultant for Boston Scientific, CVRx. and Medtronic. Dr Habecker is a co-inventor of a technology (intracellular sigma peptide) that Oregon Health and Science University has licensed to NervGen Pharma Corp. Dr Handoko has received research funding from Vifor Pharma; and has been a consultant for Novartis, Boehringer Ingelheim, Vifor Pharma, AstraZeneca, Bayer, MSD, Daiichi Sankyo, and Quin. Dr Hummel has been a scientific advisory board member; and holds equity in Nuvaira, Inc. Dr Redline has received consulting fees from Jazz Pharmaceuticals and Apnimed Inc. Dr Redline has received research funding from Jazz Pharmaceuticals. Dr Somers has served as a consultant for Bayer, Respicardia, Baker Tilly, and Jazz Pharmaceuticals; and has served on the scientific advisory board of the Sleep Number Corporation. Dr Shivkumar is a cofounder and equity holder of NeuCures Inc. Dr Simon is supported in part by NIH grant R01 AG058659, serves on a clinical trial steering committee for Janssen, and has consulted for Acceleron and Bial. Dr Mehra is supported by NIH grants U01HL125177, UH3HL140144 and the American Heart Association AHA 18SFRN34170013. Dr Arora is supported by NIH grants R01 HL140061, R01 HL125881, Technology Development Program, NIH Center for Accelerated Innovations at Cleveland Clinic, the American Heart Association Strategically Focused Research Networks Atrial Fibrillation Center, and has ownership interest in Rhythm Therapeutics, Inc. Dr Handoko is supported by the Dutch Heart Foundation (Senior Clinical Scientist grant 2020T058); has received research funding from Vifor Pharma; and has been a consultant for Novartis, Boehringer Ingelheim, Vifor Pharma, AstraZeneca, Bayer, MSD, Daiichi Sankyo, and Quin. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

**Central Illustration**
Main Tenets Highlighted The premise of the workshop is based upon a need to articulate gaps and research priorities specific to the ANS—responsible for regulation of cardiac, vascular, and pulmonary physiology via maintaining a balance of sympathetic and parasympathetic outputs to the heart, vasculature, and lungs in response to stimuli. The ANS plays a key role in the development and progression of cardiopulmonary disease and in sleep and circadian rhythm pathophysiology. Aff = afferent; ANS = autonomic nervous system; DRG = dorsal root ganglia; HR = heart rate; ParaSNA = parasympathetic nerve activity; SNA = sympathetic nerve activity.

**Figure 1**
Fundamental Mechanisms of Neural Signaling in Development and Progression of Cardiopulmonary Disease Normal cardiopulmonary reflexes are disrupted in disease, leading to increased sympathetic and decreased parasympathetic transmission. Injury activates afferent nerves that mediate sympathoexcitatory-positive feedback reflexes that contribute to myocardial and/or lung injury. We do not adequately understand **(clockwise from top)** the electrophysiological and biophysical properties of autonomic ganglia; the impact of sex as a biological variable; how to distinguish the roles of ganglionic versus systemic inflammation in neural remodeling; the mechanisms that drive afferent and efferent remodeling during disease; how to integrate clinical data from a variety of sources, scales, and modalities to guide therapy for specific patients; and the nature of interactions between cardiac and pulmonary nerves.

**Figure 2**
ANS-Related Pathophysiology of HF Heart failure (HF) is associated with significant neural remodeling characterized by increased sympathetic and reduced parasympathetic nerve activity. The **central panel** shows that the autonomic nervous system (ANS) remodeling contributes to the pathophysiology of heart failure and affects the clinical outcomes. The **left panel**, adapted from Goldstein (201) shows a concept diagram relating stress to chronic disorders such as heart failure that involve autonomic effectors. Stress is a condition in which a homeostatic comparator senses a discrepancy between afferent information to the brain about a monitored variable and a set point or other instructions for responding. The error signal drives effectors including components of the autonomic nervous system in a manner that reduces the discrepancy. Cumulative wear and tear (allostatic load) decreases effector efficiency, eventually precipitating dyshomeostatic vicious cycles. Feed-forward anticipatory processes shift input–output curves determined by the “Regulator.” The **right panel** shows major types of sensory afferent nerves and the corresponding abnormalities in autonomic reflexes observed in heart failure are illustrated. Sympathoexcitatory afferents are shown in **green**; sympathoinhibitory afferents in **blue**. Examples of underlying mechanisms acting at sensory, central, efferent, and effector organ sites that contribute to the reflex cardiovascular/respiratory dysregulation are noted. Aff = afferent; DRG = dorsal root ganglia; HR = heart rate; ParaSNA = parasympathetic nerve activity; SNA = sympathetic nerve activity.

**Figure 3**
ANS and Atrial Arrhythmias Research opportunities to reveal mechanisms by which the autonomic nervous system contributes to the development and maintenance of atrial arrhythmias. New therapeutic targets of neuromodulation and approaches to neuromodulation are depicted. AF = atrial fibrillation; ANS = autonomic nervous system; ICNS = intrinsic cardiac nervous system.

**Figure 4**
Neurophysiological Aspects of Ventricular Arrhythmias Overview of the neuromyocardial interplay and its impact on ventricular electrophysiology and arrhythmogenesis. Key features of sympathetic ventricular control are highlighted. Remodeling of the parasympathetic nervous system in cardiovascular disease has received significantly less attention (compared to sympathetic remodeling) and may also represent a therapeutic target. Research priorities with the need to address: 1) structural and functional neuronal remodeling; 2) temporal relationship between nerve activity, arrhythmia and autonomic modulation; 3) sex and racial differences; 4) population/patient-centered chronotherapies/lifestyle modification; and 5) reliable prognostic indicators are summarized. Modified from Goldberger et al (202). DAD = delayed after depolarization; EAD = early after depolarization; NGF = nerve growth factor; SCD = sudden cardiac death; VF = ventricular fibrillation; VT = ventricular tachycardia.

**Figure 5**
ANS Alterations in Cardiopulmonary-Related Sleep Disorders Autonomic nervous system (ANS) function is influenced by sleep–wake **(left)** and circadian **(right)** rhythms. Obstructive sleep apnea (OSA) is influenced by the ANS (although to a variable degree according to specific endotype) and also alters ANS function. Autonomic dysfunction (AD) resulting from these factors influence cardiovascular function, including the time predilection for arrhythmias, diurnal blood pressure patterns, and cardiac events. Knowledge gaps (in **circles**) reflect the need for an improved understanding of the interactions of sleep, circadian and cardiovascular processes, and mediating roles of the ANS. Diagnostic, prognostic, mechanistic, and treatment needs follow these gaps. CVD = cardiovascular disease; NREM = non-rapid eye movement; PSG = polysomnography; REM = rapid eye movement; ROS = reactive oxygen species; SCD = sudden cardiac death; SDB = sleep disordered breathing.

**Figure 6**
Neurophysiological Mechanisms in Pulmonary Disease and Interaction with Cardiac Function Schematic showing the knowledge gaps associated with the neurophysiological mechanisms in pulmonary diseases and their interaction with cardiac function. **Red arrows** denote physiological and pathophysiological interactions. **Green arrows** denote research implications. G labels **(blue)** denote the knowledge gaps identified in the main text. CNS = central nervous system; COPD = chronic obstructive pulmonary disease; PAH = pulmonary arterial hypertension.

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References

1. Hadaya J., Ardell J.L. Autonomic modulation for cardiovascular disease. Front Physiol. 2020;11:617459. - PMC - PubMed
1. Carandina A., Rodrigues G.D., Di Francesco P., et al. Effects of transcutaneous auricular vagus nerve stimulation on cardiovascular autonomic control in health and disease. Auton Neurosci. 2021;236:102893. - PubMed
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[1] Hadaya J., Ardell J.L. Autonomic modulation for cardiovascular disease. Front Physiol. 2020;11:617459. - PMC - PubMed

[2] Hadaya J., Ardell J.L. Autonomic modulation for cardiovascular disease. Front Physiol. 2020;11:617459. - PMC - PubMed

[3] Carandina A., Rodrigues G.D., Di Francesco P., et al. Effects of transcutaneous auricular vagus nerve stimulation on cardiovascular autonomic control in health and disease. Auton Neurosci. 2021;236:102893. - PubMed

[4] Carandina A., Rodrigues G.D., Di Francesco P., et al. Effects of transcutaneous auricular vagus nerve stimulation on cardiovascular autonomic control in health and disease. Auton Neurosci. 2021;236:102893. - PubMed

[5] Joyner M.J. Preclinical and clinical evaluation of autonomic function in humans. J Physiol. 2016;594:4009–4013. - PMC - PubMed

[6] Joyner M.J. Preclinical and clinical evaluation of autonomic function in humans. J Physiol. 2016;594:4009–4013. - PMC - PubMed

[7] Herring N., Kalla M., Paterson D.J. The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies. Nat Rev Cardiol. 2019;16:707–726. - PubMed

[8] Herring N., Kalla M., Paterson D.J. The autonomic nervous system and cardiac arrhythmias: current concepts and emerging therapies. Nat Rev Cardiol. 2019;16:707–726. - PubMed

[9] Shivkumar K., Ajijola O.A., Anand I., et al. Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J Physiol. 2016;594:3911–3954. - PMC - PubMed

[10] Shivkumar K., Ajijola O.A., Anand I., et al. Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J Physiol. 2016;594:3911–3954. - PMC - PubMed

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Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation: A Report From the National Heart, Lung, and Blood Institute and the National Institutes of Health Office of the Director Workshop

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Research Opportunities in Autonomic Neural Mechanisms of Cardiopulmonary Regulation: A Report From the National Heart, Lung, and Blood Institute and the National Institutes of Health Office of the Director Workshop

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