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Project

When environment meets genetics: the role of epigenetics in patients with chronic fatigue syndrome and fibromyalgia

Chronic pain is a debilitating condition for the individual and a huge burden for health societies all over the world. Chronic pain costs more than 600 billion dollars annually in the US, more than cancer, diabetes and heart diseases; and accounts for over 20% of healthcare expenditures in Europe. 

These data strongly highlight the need of an effective approach, that would improve the understanding and management of chronic pain. It is now well recognized that pain is neither associated to nociception nor it is a good indicator of the state of the body tissues. Cognitive, psychological and societal aspects are all able to influence pain.

The need of a more comprehensive model – that included all the aforementioned features – led to the concept of Central Sensitisation (CS). CS is a form of maladaptive neuroplasticity and represents a functional state in which the central nervous system (CNS) is over-active and hyper-responsive to stimuli. 8 CS has been extensively explored and proposed as underlying mechanism of most chronic pain conditions. CS seems able to explain most symptoms that are often reported in people with chronic pain, including the widespread distribution of pain, exaggerated response to external stimuli (e.g., visual, tactile, or noxious) or physiological/psychological stress.

Finding the best treatment approach, able to reduce CS, is therefore a major challenge, with potentially true direct benefits for patients in pain. Successful treatments necessarily rely on accurately identifying and targeting the underlying mechanisms.

 

CENTRAL SENSITIZATION & BDNF

Numerous mechanisms have been explored to biologically understand CS. We now know that CS is a plastic and reversible state of the CNS. In fact, growing evidence is focussing on brain plasticity to understand pain mechanisms, and some treatments like centrally-acting drugs and cognitive behavioural therapy have some efficacy.

Brain-derived Neurotrophic Factor (BDNF) is fundamental for CNS functions and brain plasticity. It is protein, part of the neurotrophins family, encoded by the BDNF gene and chiefly expressed in the CNS. BDNF is largely known for its major role in neural development and synaptic activity, and to promote functions like learning and memory. Other evidence shows BDNF to play a key role in maladaptive plasticity too, augmenting nociceptive inputs in peripheral nerves, spinal cord and the brain – therefore facilitating and maintaining CS.

Of note, moderate aerobic exercise is known to increase BDNF levels in humans. Similarly, exercise has also been showed to worsen pain symptoms in people with chronic widespread pain. Exercise would therefore represent an excellent way to explore the link between BDNF and CS in chronic pain patients (see Figure 1). Although a link between BDNF and CS appears evident and has been established in animal studies, it has never been explored in humans.

 

THE BDNF PATHWAY: CRUCIAL (BUT UNEXPLORED) ROLE OF EPIGENETICS

Some studies explored the association between BDNF and chronic pain in humans. Cross-sectional studies showed that BDNF is higher in blood and cerebrospinal fluid in patients with fibromyalgia, migraine or osteoarthritis. However, the mechanisms underlying BDNF increase are unknown. A common polymorphism of BDNF gene (val66met) has been studied, but results are not always consistent. In fact, even though some association was found between the BDNF gene and chronic pain severity, the polymorphism could not explain the level of BDNF protein expression.

It is in fact becoming clear that most chronic diseases are a consequence of complex gene-environment interactions. Epigenetics refers to inheritable changes in gene expression without alteration of the gene structure. It can represent the missing link between genetic variability and protein expression. The study of epigenetics has led to breakthrough findings and innovative treatments in neurology, psychiatry and oncology (e.g., new treatments for leukemia).

Growing evidence suggests that DNA methylation – a crucial epigenetic mechanism that interferes with DNA transcription –  correlates with clinical pain. Global (genome-wide) methylation is strongly associated with pain scores in an animal model of chronic pain.Specific BDNF gene methylation and demethylation are implicated in brain-related plasticity like fear conditioning, and in pain hypersensitivity in animals. In addition, neurological disorders like dementia are linked to epigenetic suppression of hippocampal BDNF. Finally, depression has also been linked to epigenetic alterations on the BDNF gene.

 

AIM

The first primary aim is to investigate whether DNA methylation of BDNF differs between patients with chronic widespread pain and healthy sedentary controls (HC). We expect patients to show a lower level of BDNF methylation when compared to controls. We also expect that methylation levels are associated with patients’ pain symptoms and with the amount of CS. This research aim will be explored in Study I. The second primary aim is to determine the effect of BDNF methylation changes in response to exercise on CS in patients with chronic widespread pain. This will be explored through an experimental study design (randomized controlled design). We will use an aerobic exercise, that has been shown capable of augmenting BDNF expression in chronic widespread pain patients.

Date:8 Jun 2017 →  19 Nov 2020
Keywords:Pain, BDNF, Epigenetics
Disciplines:Public health care, Microbiology, Systems biology, Laboratory medicine
Project type:PhD project