Role of the Brain-Lung Axis in Fatigue Y.S. Prakash, M.D., Ph.D. Professor of Anesthesiology and Physiology Chair, Department of Physiology & BME Mayo Clinic Rochester, Minnesota, USA Fatigue in Chronic Diseases Royal Netherlands Academy of Arts and Sciences November 29, 2016
Outline Defining Fatigue Fatigue and the Lung Brain-Respiratory Muscle Axis Brain-Lung Axis Questions for the Future
Defining Fatigue Highly subjective and multidimensional experience Physiologically interpreted as inability to maintain power output perceived as sensation of weakness or need for greater effort Peripheral fatigue Neuromuscular junctions and muscle responses to CNS stimulation Central Fatigue Developing in the CNS and arising from progressive failure to transmit neuronal impulses Difficulty in the initiation or maintenance of voluntary activities Absence of cognitive failure or motor weakness Linkage of peripheral to central aspects Central sensation of fatigue arising from peripheral signals mediated by afferents Activation or inhibition of central pathways Relationship between peripheral and central mechanisms not clear
Fatigue and the Lung Fatigue of maintaining respiratory forces Development and aging COPD Asthma Fatigue in maintaining airflow Asthma and bronchitis COPD Fibrosis
Lung disease and fatigue Fatigue is a given with lung disease Failing respiratory efforts due to muscle weakness and fatigue Failing respiratory efforts in the context of airflow obstruction How to measure fatigue? Asthma control questionnaire: No Asthma QOL questionnaire: Maybe Nijmegen Clinical Screening Instrument: Yes Limitations What do clinical studies tell us about mechanisms?
Lung disease and fatigue Peripheral vs. central mechanisms important in linking brain to the lung Innervation Local and Circulating Factors NMJ/Skeletal Muscle Schematics from ScienceSlides (VisiSciences Inc.)
Brain-Respiratory Muscle Axis Diaphragm and intercostal muscles Fatigue and respiratory muscle function Aging Severe asthma COPD, Critical illness, Undernutrition Drugs Cervical spinal cord injury
Aging and Breathing
Motor Units Motor Neuron Size Order of Recruitment Muscle Fiber Type Force & Fatigability Burke J Physiol, 1967; Burke et al, Science 1971; Fournier and Sieck, J Neurophysiol 1988
Activation of Diaphragm Motor Units Across Different Maneuvers Sieck and Fournier, J Appl Physiol 1989; Mantilla and Sieck, Resp Physiol Neurobiol 2011
Aging Impairs of Diaphragm Muscle Ability For High Force Production Greising et al. Resp Physiol & Neurobiol, 2015
Diaphragm Muscle Strength Decreases with Aging Polkey et al. Am J Resp Crit Care Med 155:1560, 1997
Diaphragm Muscle Fatigue Resistance Increases with Aging Greising, SM et al. Am J Physiol Lung Cell Mol Physiol 309:L46, 2015
Neuromuscular Transmission Failure Increases With Aging Interpretation: Fatigue with aging (or other conditions) may represent worsened ability of neuromuscular junction to conduct central impulses Elliott, JE et al. Respir Physiol Neurobiol 226:137, 2015 6
Can We Improve Fatigue at the Respiratory Muscle Level? Gary Sieck, PhD BDNF NT4 Carlos Mantilla, MD, PhD Elliott et al. Resp Physiol Neurobiol, 2016
The Neurotrophins Initial recognition in nerve outgrowth over 50 years ago (Levi-Montalcini, Hamburger) From the Greek (trophe: nourishment) Nutritive, target-derived factor Promote growth and survival of neurons The neurotrophin family: Nerve growth factor (NGF) Brain-derived neurotrophic factor (BDNF) Neurotrophin-3 (NT-3) Neurotrophin-4 (NT-4)
Neurotrophin Secretion Prakash and Martin Pharmacol Therap, 2014
Neurotrophin and Receptor Interactions Prakash and Martin Pharmacol Therap, 2014 Neurotrophin Receptors Tropomyosin related kinase (Trk): High Affinity p75ntr (TNF receptor family): Low Affinity Preferred ligands for specific Trk receptor subtypes p75ntr binds all neurotrophins
Can We Improve Fatigue at the Respiratory Muscle Level? Elliott et al. Resp Physiol Neurobiol, 2016
Can We Improve Fatigue at the Respiratory Muscle Level? Control Mantilla et al. J Neurosci Meth, 2009 Mantilla et al. Exp Neurol, 2013
Are Neurotrophins Relevant to Other Conditions of Fatigue? Brain and circulating BDNF may be important (17 ng/ml baseline which is physiologically effective) Decreased BDNF is associated with fatigue Prostate and breast cancer Sleep deprivation Aging Increased BDNF Improves cognition Improves depression Decreases stress Improves muscle strength (exercise, MS, Huntington s) Exercise increases circulating and brain BDNF levels
Brain-Lung Axis
Central Fatigue Factors and Lung Serotonin (5-HT) 5-HT controls appetite, sleep, memory, CV function etc. Chronic fatigue thought to involve increased brain 5-HT and/or receptors Reduced somatomotor drive Modified hypothalamic pituitary adrenal (HPA) axis function (cortisol) Sensation of reduced physical work capacity Exercise increases brain 5HT (increased transfer of circulating tryptophan into brain) 5-HT improves exercise endurance
Central Fatigue Factors and Lung Serotonin (5-HT) 5-HT is involved in asthma Increased by asthma triggers Acts on immune cells and airway smooth muscle Modulates lung cytokine environment (Yet 5HT2A receptors are anti-inflammatory and 5- hydroxytyrophan reduces inflammation) High 5-HT levels in asthmatics 5-HT is associated with depression in asthmatics and in COPD
Central Fatigue Factors and Lung Serotonin (5-HT) Chicken vs. egg? Source vs. target of 5-HT in brainlung axis? Does enhanced neuronal 5-HT influence lung structure and function in asthma? Does inflammation in lung disease modulate circulating or brain 5-HT? TNFα: relevant to asthma induction and in elderly IL-6: increasing relevance to asthma in the elderly Fatigue 5-HT 5-HT FcεRI Asthma? Fatigue
Central Fatigue Factors and Lung TNFα Fatigue correlates to inflammation levels in: Cancers Multiple sclerosis Rheumatoid arthritis TNF well-known inflammatory cytokine with role in asthma, COPD and PF Immune modulation Airway contractility and remodeling Modulates TGFbeta signaling Does lung or circulating level of TNF influence the CNS? TNF inhibits CNS neurotransmission Interesting feedback relationship between 5-HT and TNF TNF can increase brain 5HT uptake 5-HT should ideally decrease TNF Does enhanced neuronal 5HT influence lung TNF?
Central Fatigue Factors and Lung IL-6 Increasing recognition of role in Asthma, especially in the elderly Modulates pro-fibrotic signaling Fatigue correlates to IL-6 levels in: Elderly patients Breast cancer (in association with infection) Does lung or circulating level of IL-6 influence the CNS?
Central Fatigue Factors and Lung HPA Axis Well-known decrease in cortisol levels with chronic fatigue Physical and/or psychological stresses tend to increase CRH Chronic inflammation tends to reduce CRH synthesis and release. Asthma is associated with decreased cortisol levels Decreased cortisol allow for increased inflammation YET Pro-inflammatory cytokines (TNF, IL-6) are stimulators of HPA axis 5-HT should stimulate cortisol Does increased lung inflammation contribute to reduced cortisol? Does oral steroid therapy alter fatigue symptoms in asthmatics? Need to differentiate effects on improved asthma control, stress, sleep disruption etc. Steroids also suppress endogenous HPA axis
Central Fatigue Factors and Lung Stress Known to worsen asthma Stress in asthmatics adversely affects control Stress increases 5-HT, TNF, IL-6, IL1, and even BDNF Altered HPA axis Complex effects on immune system and airway function
Central Fatigue Factors and Lung Vagal Innervation Afferents to brainstem Efferent parasympathetics to airways Vagal afferents reflex inhibit somatomotor activity normally limits exercise in the presence of pulmonary edema Decreased skeletal muscle activity would be perceived as fatigue 5-HT, TNF, IL-6 and even BDNF can stimulate vagal afferents Vagal afferents mediate sickness behavior by cytokines Occurs in response to infection Symptoms such as fatigue, increased sleep, fever etc. Vagal nerve mediates induction of brain IL-1β in response to peripheral IL-1β
Central Fatigue Factors and Lung Neurotrophins May be beneficial in the CNS Central stress regulator Potential to decrease muscle fatigue BUT Likely to be detrimental in the lung
Neurotrophins in the Lung Prakash et al. Expert Rev Resp Med, 2012
Brain-Lung Axis and Fatigue Central Fatigue Neurotransmitters Growth Factors Inflammation FcεRI Aging Co-Morbidity Peripheral Fatigue