Abstract
Objectives: Therapeutic effects of physical therapy in neurologic disorders mostly rely on the promotion of use-dependent synaptic plasticity in damaged neuronal circuits. Genetic differences affecting the efficiency of synaptic plasticity mechanisms could explain why some patients do not respond adequately to the treatment. It is known that physical exercise activates the endocannabinoid system and that stimulation of cannabinoid CB1 receptors (CB1Rs) promotes synaptic plasticity in both rodents and humans. We thus tested whether CB1R genetic variants affect responsiveness to exercise therapy.
Methods: We evaluated the effect of a genetic variant of the CB1R associated with reduced receptor expression (patients with long AAT trinucleotide short tandem repeats in the CNR1 gene) on long-term potentiation (LTP)–like cortical plasticity induced by transcranial magnetic theta burst stimulation (TBS) of the motor cortex and, in parallel, on clinical response to exercise therapy in patients with multiple sclerosis.
Results: We found that patients with long AAT CNR1 repeats do not express TBS-induced LTP-like cortical plasticity and show poor clinical benefit after exercise therapy.
Conclusions: Our results provide the first evidence that genetic differences within the CB1R may influence clinical responses to exercise therapy, and they strengthen the hypothesis that CB1Rs are involved in the regulation of synaptic plasticity and in the control of spasticity in humans. This information might be of great relevance for patient stratification and personalized rehabilitation treatment programs.
GLOSSARY
- AATn=
- AAT trinucleotide short tandem repeat;
- AMT=
- active motor threshold;
- ANOVA=
- analysis of variance;
- CB1R=
- cannabinoid CB1 receptor;
- CS=
- conditioning stimulus;
- DMD=
- disease-modifying drug;
- EAE=
- experimental autoimmune encephalomyelitis;
- EDSS=
- Expanded Disability Status Scale;
- FDI=
- first dorsal interosseus muscle;
- FLAIR=
- fluid-attenuated inversion recovery;
- ICF=
- intracortical facilitation;
- ISI=
- interstimulus interval;
- iTBS=
- intermittent TBS;
- LICI=
- long-interval intracortical inhibition;
- LTP=
- long-term synaptic potentiation;
- MEP=
- motor evoked potential;
- MS=
- multiple sclerosis;
- NRS=
- Numerical Rating Scale;
- pp=
- paired-pulse;
- PT=
- physical therapy;
- RMT=
- resting motor threshold;
- RRMS=
- relapsing-remitting MS;
- SICF=
- short-interval intracortical facilitation;
- SICI=
- short-interval intracortical inhibition;
- TBS=
- theta burst stimulation;
- TMS=
- transcranial magnetic stimulation;
- TS=
- test stimulus;
- TSE=
- turbo spin echo
Footnotes
Go to Neurology.org/nn for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was paid by Dipartimento di Medicina dei Sistemi, Facoltà di Medicina e Chirurgia, Università degli Studi di Roma Tor Vergata, Rome, Italy.
- Received June 23, 2014.
- Accepted in final form October 21, 2014.
- © 2014 American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
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