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Fatigue in Chronic Diseases Royal Netherlands Academy of Arts and Sciences
November 29, 2016
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
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
NMJ/Skeletal Muscle
Local and Circulating Factors
Innervation
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
Burke J Physiol, 1967; Burke et al, Science 1971; Fournier and Sieck, J Neurophysiol 1988
Motor Neuron Size – Order of Recruitment
Muscle Fiber Type – Force & Fatigability
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
Interpretation: Fatigue with aging (or other conditions) may represent worsened ability of neuromuscular junction to conduct central impulses
Neuromuscular Transmission Failure Increases With Aging
Elliott, JE et al. Respir Physiol Neurobiol 226:137, 2015 6
Can We Improve Fatigue at the Respiratory Muscle Level?
Elliott et al. Resp Physiol Neurobiol, 2016
BDNF NT4
Gary Sieck, PhD
Carlos Mantilla, MD, PhD
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
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
Prakash and Martin Pharmacol Therap, 2014
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?
Mantilla et al. J Neurosci Meth, 2009
Control
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
Chicken vs. egg? Source vs. target of 5-HT in brain-
lung 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
Central Fatigue Factors and Lung Serotonin (5-HT)
5-HT
FcεRI
5-HT
Asthma?
Fatigue
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
FcεRI
Central Fatigue
Inflammation
Peripheral Fatigue
Neurotransmitters Growth Factors
Aging Co-Morbidity
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