A Modifiable Piece of the ME/CFS Puzzle: BDNF

This article was originally published on Health Rising on June 11th 2014.


Leading ME/CFS researcher Lenny Jason and his group just released a novel study showing that the protein Brain Derived Neurotrophic Factor (BDNF)   was below normal levels in Chronic Fatigue Syndrome patients (1). This study provides another biomarker that validates the illness as real and organic. But, most importantly, it presents another modifiable piece of the complex puzzle of CFS.

What is BDNF?

BDNF is a central nervous system growth factor protein coded for by a gene of the same name. The BDNF gene is expressed in the greatest quantity in the dorsal vagal complex and the dorsal motor nucleus of the vagus—both housed in the hypothalamus. A new theory posed by neuroscientist VanElzakker, suggested that infections may migrate via the vagus nerve and perpetuate ME/CFS symptoms (2). If correct, this theory may also encompass BDNF gene activity in these key vagal areas in the brain.

In the body, BDNF is found primarily in serum, plasma, and platelets. It is also produced by immune cells such as lymphocytes and macrophages. To a lesser extent it circulates in cerebral spinal fluid.

BDNF acts like fertilizer for neurons—prompting sprouting of new neuronal connections in a process known as neural plasticity. Suppression of BDNF has been found to lead to neuronal atrophy within the hippocampus—a key area for memory formation and implicated in depression. Higher levels throughout life are associated with reduced risk of age-related cognitive decline from oxidative stress (3).

The BDNF-Gut Connection

In animal studies, altered gut flora is believed to regulate the HPA axis. In mice without gut flora (germ-free), the stress response is exaggerated at the HPA axis and consequent reductions in BDNF are also found. These mice exhibit impaired cognition and increased stress as measured by plasma neurotransmitters. One study reintroduced the bacterial species B. longum which normalized BDNF levels and reduced markers of stress (4).

The mechanism in animals is believed to be mediated by the vagus nerve, which directly links the gut to the brain—a gut-brain axis. As mentioned above, the densest concentration of BDNF genes are found in vagus nerve nuclei in the hypothalamus, further supporting that bacterial species can migrate or perpetuate their effects via this important cranial nerve.

BDNF’s Role in Fibromyalgia

Many studies have been conducted that measure BDNF in fibromyalgia. Interestingly, the majority of these studies reveal increased levels of serum BDNF in fibromyalgia patients. Here, BDNF appears to influence painful sensory input and hypersensitivity (5). This could be a defining characteristic that differentiates CFS from Fibromyalgia.

BDNF’s Role in ME/CFS

An advanced imaging study in ME/CFS found widespread neuroinflammation in various key brain regions including the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons. Inflammation in these areas was 45%-199% times higher in ME/CFS patients than in healthy controls (6). Since neuroinflammation leads to oxidative stress and mitochondrial damage, it is reasonable to extrapolate this data and speculate that BDNF levels would be reduced in this cohort of patients if measured.

The only other study examining this comes from an animal model of ME/CFS. Decreased BDNF was associated with brain atrophy and cell death at the hippocampus. When these animals were given therapeutic BDNF stimulants, hippocampal size increased and daily activity level increased (7).

Simple Ways to Raise BDNF

Caloric restriction and intermittent fasting promote cellular pathways that reduce oxidative stress and raise BDNF levels (sirtuin family of genes). Rodent studies where the diet consisted of high sugar, “junk food” rat chow, resulted in greatly reduced BDNF levels and increased oxidative stress (3).

Get Some Sun

Animal studies show reduced BDNF levels with light deprivation. A 2012 human study described the seasonal variation of serum BDNF levels in a European cohort. Results indicated that BDNF concentrations have seasonal variation—levels increased over the course of the spring and the summer and decreased over the course of the autumn and the winter. Also, there was a positive correlation between the number of sunlight hours and the concentration of serum BDNF (8).

Exercise or Learn Something New

Animal and human studies have demonstrated that moderate exercise can stimulate BDNF production and the creation of new neurons. If health allows, light aerobic exercise seems to be the best means to increase BDNF (3). Additionally, learning a new task or completing a challenging activity can promote neurogenesis through BDNF (3).

Supplements That Raise BDNF


Curcumin is widely studied as a possible drug target for Alzheimer’s disease and other neurodegenerative disorders. Many studies show this spice is a potent activator of BDNF and may even reduce amyloid beta deposition and brain atrophy—hallmarks of Alzheimer’s (3,9).

Resveratrol & Green Tea

Resveratrol is a potent antioxidant found in red grape skins. In an animal model of ME/CFS, supplementation with resveratrol raised BDNF levels and improved activity levels (7). A compound in green tea, epigallocatechin gallate (EGCG), may be a more potent stimulator of BDNF than resveratrol, however. Animal and in vitro studies comparing the two compounds show that EGCG readily crosses the blood-brain barrier and stimulates the BDNF signaling pathway (10).

Omega-3 Oils (EPA and DHA)

The long-chain, polyunsaturated fats EPA and DHA have numerous benefits for neurological health. Several studies have examined the biochemical mechanism of action of these fats and demonstrated their ability to promote BDNF expression. The cellular effect of EPA and DHA administration is the creation of new neurons as well as neuron protection via anti-inflammatory signaling (3,11).

1  Sorenson M, Jason L, Peterson J, Herrington J, Mathews H (2014) Brain Derived Neurotrophic Factor is Decreased in Chronic Fatigue Syndrome and Multiple Sclerosis. J Neurol Neurophysiol S12:S2-013. http://omicsonline.org/open-access/brain-derived-neurotrophic-factor-is-decreased-in-chronic-fatigue-syndrome-and-multiple-sclerosis-2155-9562-S12-013.pdf

2  VanElzakker MB. (2013) Chronic fatigue syndrome from vagus nerve infection: a psychoneuroimmunological hypothesis. Med Hypotheses. 81(3):414-23. Epub 2013 Jun 19. http://www.ncbi.nlm.nih.gov/pubmed/23790471

3  Gomez-Pinilla F. (2008) The influences of diet and exercise on mental health through hormesis. Ageing Res Rev. 7(1):49-62. Epub 2007 May 5. http://www.ncbi.nlm.nih.gov/pubmed/17604236

4  Wang Y, Kasper LH (2014) The role of microbiome in central nervous system disorders. Brain Behav Immun. 38:1-12. Epub 2013 Dec 25. http://www.ncbi.nlm.nih.gov/pubmed/24370461

5  Nugraha B, Karst M, Engeli S, Gutenbrunner C. (2012) Brain-derived neurotrophic factor and exercise in fibromyalgia syndrome patients: a mini review. Rheumatol Int. 32(9):2593-9. Epub 2011 Dec 31. http://www.ncbi.nlm.nih.gov/pubmed/22210272

6  Nakatomi Y, et al (2014) Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. J Nucl Med. 55(6):945-950. [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/24665088

7  Moriya J, Chen R, Yamakawa J, Sasaki K, Ishigaki Y, Takahashi T. (2011) Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells. Biol Pharm Bull. 34(3):354-9. http://www.ncbi.nlm.nih.gov/pubmed/21372384

8  Molendijk ML, et al (2012) Serum BDNF concentrations show strong seasonal variation and correlations with the amount of ambient sunlight. PLoS One. 7(11):e48046.  Epub 2012 Nov 2. http://www.ncbi.nlm.nih.gov/pubmed/23133609

9  Chen Q., et al. (2011) A novel neurotrophic drug for cognitive enhancement and Alzheimer’s disease. PLoS One. 6(12):e27865. Epub 2011 Dec 14. http://www.ncbi.nlm.nih.gov/pubmed/22194796

10  Nath S, Bachani M, Harshavardhana D, Steiner JP. (2012) Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway. J Neurovirol. 2012 Dec;18(6):445-55. Epub 2012 Aug 11. http://www.ncbi.nlm.nih.gov/pubmed/22886603

11  Su HM. (2010) Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. J Nutr Biochem. 21(5):364-73. Epub 2010 Mar 16. http://www.ncbi.nlm.nih.gov/pubmed/20233652