The Effects of Aerobic Exercise Intensity and Duration on Levels of Brain-Derived Neurotrophic Factor in Healthy Men

This study examined the combined effects of aerobic exercise intensity and duration on serum brain-derived neurotrophic factor (sBDNF) levels in healthy human adult males aged 18-25 years. Forty five participants were randomly assigned to one of six exercise conditions based on varying intensity (80% or 60% of heart rate reserve, or control) and duration (20 or 40 min). Vigorous (80% heart rate reserve, “Vig”) and moderate (60% heart rate reserve, “Mod”) exercise was carried out on cycle ergometers. Control subjects remained seated and at rest during the exercise period. Pre- and post-exercise blood draws were conducted and sBDNF measured. Physical exercise caused an average ~ 32% increase in sBDNF levels relative to baseline that resulted in concentrations that were 45% higher than control conditions. Comparing the six conditions, sBDNF levels rose consistently among the four exercise conditions (Vig20 = 26.38 ± 34.89%, Vig40 = 28.48 ± 19.11%, Mod20 = 41.23 ± 59.65%, Mod40 = 30.16 ± 72.11%) and decreased consistently among the controls (Con20 = -14.48 ± 16.50, Con40 = -10.51 ± 26.78). Vig conditions had the highest proportion of subjects that experienced a significant (? 10%) increase in sBDNF levels, followed by Mod and control conditions. An analysis of modeled sBDNF integrals (area under the curve) demonstrated substantially greater values for Vig40 and Mod40 conditions compared to Vig20 and Mod20 conditions. Collectively, these results demonstrate that neither duration (20 vs. 40 min) nor intensity (60 vs. 80% HR reserve) significantly affects the benefits of exercise if only the sBDNF increase at a single post-exercise time point is considered. However, when comparing either the probability of achieving a significant BDNF gain or the integral (i.e. the volume of circulating BDNF over time) the Vig40 condition offers maximal benefits. Thus, we conclude that the future study of aerobic exercise effects on BDNF-mediated neuroprotection should take the volume of BDNF release over time into account. Key Points Aerobic exercise caused a ~32% increase in serum BDNF in adult human males while serum BDNF decreased 13% in sedentary control subjects. Vigorous intensity (80% heart rate reserve), long duration (40 min) exercise offered the greatest probability of a significant BDNF elevation. Long duration exercise offered the greatest numerical benefits in terms of BDNF integral. Neither intensity nor duration affected the mean elevation in BDNF amplitude caused by exercise. Key words: Aerobic, brain-derived neurotrophic factor (BDNF), exercise, human, neurotrophins Introduction Brain-derived neurotrophic factor (BDNF) has been recognized as an important tropic hormone in the regulation of neuron morphology and survival. Endogenous BDNF is known to be involved in cellular development and growth, mood regulation, and cognitive functions such as learning and memory. Low circulating BDNF levels have been associated with a wide range of neuropsychiatric disorders including depression (Karege et al., 2002), bipolar disorder (Cunha et al., 2006), schizophrenia (Zhang et al., 2007) and neurodegenerative diseases (Yu et al., 2008), although no causal relationship has yet been established. Research over the past decade has investigated the factors that can acutely and chronically elevate brain levels of BDNF in animals and circulating levels of BDNF in humans, based on the assumption that elevated BDNF levels can lead to improved brain health. Research has consistently shown that chronic aerobic exercise can elevate baseline BDNF levels in the hippocampus, striatum, and various cortical regions in laboratory animals (Ding et al., 2004; Neeper et al., 1996; Oliff et al., 1998; Rasmussen et al., 2009; Vaynman et al., 2004a; Widenfalk et al., 1999), and Suijo et al., 2013 have recently demonstrated that resistance exercise can also elevate BDNF levels in the hippocampus. Encouragingly, BDNF transcription can be induced in the rat hippocampus after only three consecutive days of aerobic exercise. Also, unlike other neurotrophic factors which showed tolerance to chronic exercise, BDNF levels remained upregulated in the rat hippocampus after 28 consecutive days of wheel running (Molteni et al., 2002). In animal models of disease, chronic exercise has provided BDNF benefits such as cell survival (Ang et al., 2003), decreased depressive symptoms (Marais et al., 2009), and cellular protection and functional recovery after traumatic brain injury (Griesbach et al., 2004). Furthermore, chronic aerobic exercise seems to have a robust effect on cognition, as various intensities and durations of voluntary and forced exercise have consistently improved learning and memory in healthy laboratory animals, whether assessed by Morris water maze (Adlard et al., 2004; Huang et al., 2006; Vaynman et al., 2004b), radial arm maze (Anderson et al., 2000), Y-maze (Van der Borght et al., 2007), object recognition tasks (O'Callaghan et al., 2007), or pain avoidance training (Liu et al., 2008; Radak et al., 2006). In each of these studies, an increase in BDNF mRNA or protein levels was positively associated with performance enhancement. In humans, chronic aerobic exercise has been tested for its ability to raise baseline circulating BDNF levels. Several chronic exercise studies suggest that aerobic training can increase resting levels of circulating BDNF (Seifert et al., 2010; Zoladz et al., 2008). However, the majority of chronic exercise studies, especially those not using aerobic exercise training, have not observed increased basal circulating BDNF levels (Goekint et al., 2010; Griffin et al., 2011; Levinger et al., 2008; Schiffer et al., 2009). While the impact of chronic exercise on BDNF has been extensively tested, particularly in animal studies, much less is known about the effects of a single bout of aerobic exercise on brain BDNF levels. Several animal studies have demonstrated significantly increased BDNF mRNA levels in the rat hippocampus after a single bout of six hours voluntary wheel running (Chen and Russo-Neustadt, 2009; Oliff et al., 1998). Huang et al., 2006 also reported a strong BDNF response in the hippocampus (~50% increase) of rodents after a single bout of aerobic exercise, with no difference between moderate or intense exercise. However, Klintsova et al., 2004 did not find an effect of acute moderate intensity aerobic exercise on BDNF levels in the cerebellum or motor cortex of rats; BDNF levels were elevated in the cerebellum only after five days of training and in the motor cortex after 14 days. Human research investigating the effect of acute single-bout aerobic exercise has focused on two areas in particular, either characterizing the change in serum BDNF (sBDNF) levels after one exercise session, or identifying the effects of exercise intensity on these post-exercise sBDNF levels. The acute effect of exercise on human sBDNF levels is characterized as a transient, moderate (~20-40%) increase (Gold et al., 2003; Rojas Vega et al., 2006; Tang et al., 2008). Serum BDNF levels rise during aerobic exercise, and quickly return to baseline levels upon exercise cessation, approximately 10-15 minutes after exercise offset (Rojas Vega et al., 2006; Tang et al., 2008). High intensity exhaustive aerobic exercise for a short duration (Rojas Vega et al., 2006), or sustained moderate intensity exercise (Gold et al., 2003) appear sufficient to increase sBDNF levels. Encouragingly, as little as 15 minutes of moderate intensity exercise has significantly elevated sBDNF levels in healthy human subjects (Tang et al., 2008). Ferris et al., 2007 clearly demonstrated an effect of aerobic exercise intensity on sBDNF levels using a within subjects counterbalanced design. Their report suggested that low intensity exercise was insufficient to elevate BDNF levels relative to baseline, while high intensity exercise for a comparable duration significantly elevated sBDNF levels (Ferris et al., 2007). Human studies to date have not systematically varied exercise duration across acute aerobic conditions, and only several studies have examined the impact of exercise intensity. Therefore, the present study was designed to assess for the first time the combined effects of exercise intensity and duration on sBDNF levels in young healthy adult humans and to assess the extent to which sBDNF levels can be elevated in relation to sedentary controls.