Acute increases in brain-derived neurotrophic factor in plasma following physical exercise relates to subsequent learning in older adults

Abstract

Multidomain lifestyle interventions represents a promising strategy to counteract cognitive decline in older age. Brain-derived neurotrophic factor (BDNF) is essential for experience-dependent plasticity and increases following physical exercise, suggesting that physical exercise may facilitate subsequent learning. In a randomized-controlled trial, healthy older adults (65-75 years) completed a 12-week behavioral intervention that involved either physical exercise immediately before cognitive training (n = 25; 13 females), physical exercise immediately after cognitive training (n = 24; 11 females), physical exercise only (n = 27; 15 females), or cognitive training only (n = 21; 12 females). We hypothesized that cognition would benefit more from cognitive training when preceded as opposed to followed by physical exercise and that the relationship between exercise-induced increases in peripheral BDNF and cognitive training outcome would be greater when cognitive training is preceded by physical exercise. Greater increases of plasma BDNF were associated with greater cognitive training gains on trained task paradigms, but only when such increases preceded cognitive training (ß = 0.14, 95% CI [0.04, 0.25]). Average cognitive training outcome did not differ depending on intervention order (ß = 0.05, 95% CI [-0.10, 0.20]). The study provides the first empirical support for a time-critical but advantageous role for post-exercise increases in peripheral BDNF for learning at an interindividual level in older adults, with implications for future multidomain lifestyle interventions.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1

Schematic of the study procedure. Pretest and posttest included physical fitness tests (Fitness) and assessment of acute changes in BDNF concentrations (BDNF), both performed in the morning (AM), as well as an extensive cognitive assessment completed over three afternoon sessions (Cog 1–3; PM). The pretest phase additionally included an introduction to the allocated training intervention (Intro). At the BDNF assessment, the allocated intervention was performed and three blood samples were obtained: before (S1) and after (S2) the first intervention and after the second intervention or rest (S3; see red inset). During the intervention phase, training sessions took place every second weekday (2–3 sessions/week), according to the allocated intervention: physical exercise followed by cognitive training (PE + COG), cognitive training followed by physical exercise (COG + PE), physical exercise only (PE) and cognitive training only (COG). Note that an accelerometer assessment was also conducted (not depicted) and that only the BDNF assessment at pretest was considered in the present study.

Figure 2

Recruitment diagram. Number of subjects initially screened, attending the information meeting, and subsequently consenting and being randomized into the study and completing each of the four intervention programs (PE + COG, COG + PE, PE, COG). Number of drop-outs is specified for each phase of the study procedure and reasons discontinuing the study are specified in brief (drop-out analysis, S6). Illness = illness, injury or health reasons. Scheduling = inability to adhere to the study schedule. Personal = personal reasons. Undisclosed = reason not specified. Study criteria = one or more study criteria no longer fulfilled. Intervention = dissatisfied with allocated intervention. Procedure = dissatisfied with one or more aspects of the study procedure.

Figure 3

Blood sampling protocol (A) and acute BDNF changes in response to the interventions in serum (B) and in plasma. (C) BDNF concentrations in serum increase in response to physical exercise (sample 1 to 2 in PE and PE + COG groups; sample 2 to 3 in COG + PE group) but not in response to cognitive training (sample 1 to 2 in COG and COG + PE; sample 2 to 3 in PE + COG group). BDNF concentrations in plasma increase independent of intervention. Note that the hypothesis testing involved specific group comparisons and merging of groups. PE = physical exercise, COG = cognitive training.

Figure 4

Change in working memory performance from pretest to posttest (A–C) and across cognitive training visits. (D,E) Estimated marginal means (error bars = 95% confidence intervals) derived from linear mixed models testing intervention effects on performance in trained tasks (trained stimuli), in the context of hypothesis 3 (COG + PE & PE + COG vs. COG; A), hypothesis 4 (COG + PE & PE + COG vs. PE; B) and hypothesis 1 (COG + PE vs. PE + COG; C), with spaghetti lines corresponding to individual change trajectories (T-scores, M = 50, SD = 10). Model-implied regression lines illustrating the effect of training visit on progress in the n-back task during the cognitive training intervention (maximum score = 24), in the context of hypothesis 3 (COG + PE & PE + COG vs. COG; D) and 4 (COG + PE & PE + COG vs. PE; E). COG = cognitive training, PE = physical exercise, COMB = PE and COG, irrespective of order.

Figure 5

Visualization of the differential relationship between acute BDNF change and pre-post change in trained task performance in the COG + PE and PE + COG groups. Scatterplot with individual data points and zero-order correlations between training gains (pre-post change in performance on trained tasks with untrained stimuli) and acute change in BDNF concentrations in response to physical exercise in plasma at pretest (R). A relationship between exercise-induced BDNF change and cognitive training gain only exists in the group that received physical exercise prior to cognitive training (COG + PE, pale blue). Note that the three-way interaction remains significant at the corrected α-level even when the two potential outliers in the PE + COG group are excluded, F(1,43) = 7.20, p = 0.010. The zero-order correlations also still differed significantly after such outlier removal, Fisher’s Z = 2.67, p = 0.008 (two-tailed).

Figure 6

Visualization of the relationship between acute BDNF change and pre-post change in trained task performance in the COG + PE and PE + COG groups, separate for blood sample 1 (A), 2 (B) and 3 (C). Scatterplots visualizing individual data points and zero-order correlations between training gains (pre-post change in performance on trained tasks with untrained stimuli) and acute change in BDNF concentrations in response to physical exercise in plasma at pretest, separate for the PE + COG (orange) and COG + PE (pale blue). BDNF concentrations only predict cognitive training gain in the PE + COG group and only at Sample 2.