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