Background

Brain-derived neurotrophic factor (BDNF) supports synaptic plasticity and long-term potentiation. The Val66Met polymorphism (rs6265) produces a Met allele with impaired activity-dependent BDNF secretion. Met carriers show reduced hippocampal volume and elevated Alzheimer's risk, but the acute plasticity effects matter more for rehabilitation.

Evidence for reduced motor plasticity

Kleim et al. (2006) showed that Met carriers exhibit less motor cortex excitability change after motor training. The effect size is substantial—roughly 30% less map expansion compared to Val/Val homozygotes following identical training protocols.

Cirillo et al. (2012) replicated this using transcranial magnetic stimulation to measure motor evoked potentials. Met carriers required significantly more practice to achieve equivalent motor learning gains.

Clinical implications for rehabilitation

Constraint-induced movement therapy (CIMT) protocols assume uniform plasticity capacity. They are not. Met carriers may need:

1. Extended training duration: The 6-hour daily CIMT protocol may be insufficient for Met carriers; 8-9 hours may be needed to achieve equivalent cortical reorganization

2. Adjunctive BDNF enhancement: Aerobic exercise elevates serum BDNF across genotypes, but the relative benefit is larger for Met carriers. Exercise priming before motor training may normalize plasticity responses

3. Pharmacological augmentation: Small trials suggest fluoxetine increases BDNF signaling and may partially compensate for the Met genotype. SSRIs plus training outperforms training alone in Met carriers specifically

The mechanism

Activity-dependent BDNF release normally drives TrkB receptor activation, initiating signaling cascades that stabilize synaptic changes. The Met variant reduces activity-dependent secretion by 25-30% without affecting baseline levels. This creates a threshold problem—subthreshold stimulation fails to trigger plasticity mechanisms that would engage in Val/Val individuals.

Testable predictions

1. Met carriers will show less motor cortex map expansion after standard CIMT protocols compared to Val/Val
2. Exercise priming (30min moderate aerobic activity) will increase training-induced plasticity more in Met carriers than Val/Val
3. Met carriers receiving extended-duration protocols (9hr vs 6hr) will achieve equivalent outcomes to Val/Val at standard dosing

Limitations

Most studies examine young healthy adults. Age and neurological injury may interact with the polymorphism in complex ways. The BDNF genotype is not destiny—ceiling effects exist, and motivated Met carriers can achieve full recovery with appropriate dosing.

Bottom line

Rehabilitation dosing should be personalized by BDNF genotype. One-size-fits-all protocols disadvantage Met carriers who need higher plasticity thresholds to achieve equivalent outcomes.

Research synthesis from BDNF Val66Met literature including Kleim et al. (2006), Cirillo et al. (2012), and meta-analyses of plasticity genetics.