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. 2010 Nov 22;589(Pt 2):297–306. doi: 10.1113/jphysiol.2010.200600

Plasticity in human motor cortex is in part genetically determined

Julia Missitzi 1,2, Reinhard Gentner 2, Nickos Geladas 1, Panagiotis Politis 3, Nikos Karandreas 4, Joseph Classen 2,5, Vassilis Klissouras 1
PMCID: PMC3043534  PMID: 21098007

Abstract

Brain plasticity refers to changes in the organization of the brain as a result of different environmental stimuli. The aim of this study was to assess the genetic variation of brain plasticity, by comparing intrapair differences between monozygotic (MZ) and dizygotic (DZ) twins. Plasticity was examined by a paired associative stimulation (PAS) in 32 healthy female twins (9 MZ and 7 DZ pairs, aged 22.6 ± 2.7 and 23.8 ± 3.6 years, respectively). Stimulation consisted of low frequency repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with a single pulse transcranial magnetic stimulation (TMS) for activation of the abductor pollicis brevis muscle (APB). Corticospinal excitability was monitored for 30 min following the intervention. PAS induced an increase in the amplitudes of the motor evoked potentials (MEP) in the resting APB, compared to baseline. Intrapair differences, after baseline normalization, in the MEP amplitudes measured at 25–30 min post-intervention, were almost double for DZ (1.25) in comparison to MZ (0.64) twins (P = 0.036). The heritability estimate for brain plasticity was found to be 0.68. This finding implicates that genetic factors may contribute significantly to interindividual variability in plasticity paradigms. Genetic factors may be important in adaptive brain reorganization involved in motor learning and rehabilitation from brain injury.

Non-technical summary

Neuronal plasticity refers to the ability of the brain to change in response to different experiences. Plasticity varies between people, but it is not known how much of this variability is due to differences in their genes. In humans, plasticity can be probed by a protocol termed paired associative stimulation and the changes in the motor system that are brought about by such stimulation are thought to be due to strengthening synapses which connect different neurons. We examined pairs of sisters which were either genetically identical (monozygotic) or different (dizygotic). We found that the variability within the monozygotic sister pairs was less than the variability within the dizygotic sister pairs. That plasticity in human motor cortex is in a substantial part genetically determined may be relevant for motor learning and neurorehabilitation, such as after stroke.

Introduction

The adult brain maintains the ability to modify its organization through physiological mechanisms, such as synaptic plasticity, in response to various injuries (Donoghue et al. 1990; Sanes et al. 1992; Brazil-Neto et al. 1993), environmental changes (Pascual-Leone et al. 1995; Pearce et al. 2000; Stefan et al. 2000; Latash et al. 2003; Perez et al. 2004) and even repetitions of simple movements (Classen et al. 1998). In a changing environment, brain plasticity enables the nervous system to ensure that proper activation of muscles may be acquired and maintained to serve the behavioural goal. Major advances have been made within the past 20 years in understanding the mechanisms involved in brain plasticity (Sanes & Donoghue, 2000; Nudo, 2006). In motor plasticity paradigms, several behavioural factors (e.g. initial level of proficiency, rate of improvement and final level of attainment) have been identified as influencing the variability of individual response to the plasticity inducing protocol (Wassermann 2002; Müller-Dahlhaus et al. 2008; Sale et al. 2008), the different functional outcomes after neurological injury (Noyes et al. 1983), and the effectiveness of rehabilitation or training (Fox et al. 1996). However, little is known about the magnitude of genetic determinants of the variability observed in these complex phenotypes.

Recently, a genetic component has been observed for brain plasticity, as individuals with the val66met polymorphism in the brain derived neurotrophic factor (BDNF) gene show less increase in the motor evoked potentials (MEPs) after motor training (Kleim et al. 2006). Cheeran and colleagues (2008) extended this observation, by using paired associative stimulation (PAS), a protocol intended to model synaptic plasticity in humans (Müller-Dahlhaus et al. 2010). These authors found that the susceptibility to TMS probes was significantly influenced by the BDNF polymorphism in the normal population, suggesting that BDNF signalling is a major factor influencing synaptic plasticity (Cheeran et al. 2008). Although these studies have provided proof-of-principle evidence that synaptic plasticity may be genetically influenced, independent and complementary information could be gained from twin studies. Without previous assumptions of the genes involved, a twin study design allows the discrimination between environmental and genetic effects of any genotype.

Therefore, the aim of this study was to assess the relative power of genetic and environmental contribution to the variation observed in brain plasticity by selecting a sufficiently homogeneous sample of monozygotic (MZ) and dizygotic (DZ) twins and comparing the intrapair differences between the two types of twins. Plasticity in this study was examined by paired associative stimulation, which has been shown to alter excitability, in the human motor cortex, by mechanisms related to synaptic long term potentiation (LTP).

Methods

Subjects

Thirty-two healthy female twins (9 MZ and 7 DZ pairs, aged 22.6 ± 2.7 and 23.8 ± 3.6 years, respectively) from a university student population were invited to participate in this study. Twins were fully informed about the protocol before giving their written consent. Since environmental comparability is a fundamental assumption made in the twin model, special attention was given to a large variety of potential confounding factors. For this purpose a questionnaire was administered regarding physical activity profiles, sport participation, socioeconomic status, occupational physical loading of the upper extremity, and health condition, to ensure that environmental influences were comparable in both types of twins. Since all twins were women, the questionnaire also included information about the age of menarche and about menstrual cycle (duration, timing and flow). All volunteers were right handed, except one twin pair, who were left handed according to the Oldfield handedness inventory (Oldfield, 1971). Only healthy subjects were allowed to participate in the study. The protocol was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics committees of the Universities of Würzburg and Athens.

Zygosity was assessed at first approximation through direct observation of relevant morphological characteristics, physical similarities and the testimony of the obstetrical archives (Chen et al. 1999; Kasriel & Eaves, 1976), and subsequently confirmed by serological examination of genetic markers in all twins. Discordance for a single antiserum was regarded as sufficient evidence of dizygosity (Sutton et al. 1962).

BDNF genotyping technique

Genotyping was carried out twice in 14 subjects. Genomic DNA was extracted from leukocytes by standard DNA extraction procedure. A 113 bp segment was amplified by polymerase chain reaction (PCR), using the following primers: 5′-GAGGCTTGACATCATTGGCT-3′ and 5′-CGTGTACAAGTCTGCGTCCT-3′. Target sequences were amplified in a 50 μl reaction solution containing 100 ng genomic DNA; 1 U Taq polymerase (Bioron, Ludwigshafen, Germany); 20 mm Tris-HCl (pH 8.4); 50 mm KCl; 1.5 mm MgCl2; 200 mm each of dATP, dCTP, dGTP and dTTP; and 10 pmol of each primer. After an initial denaturation of the DNA templates for 5 min at 95°C, 30 cycles were performed, each consisting of 94°C for 30 s, 60°C for 30 s, and 72°C for 30 s. After the last cycle, samples were incubated at 72°C for 5 min. Samples were then digested overnight with 3 U of NlaIII (MBI Fermentas, Burlington, Ontario, Canada). The fragments were separated on a 3% agarose gel at 100 V, and fragments were visualized with ethidium bromide (Neves-Pereira et al. 2002).

Stimulation

Focal transcranial magnetic stimulation (TMS) was performed using a flat figure of eight shaped magnetic coil (outer diameter of each wing: 70 mm) connected with a Magstim 200 monophasic magnetic stimulator (Magstim, Whitland, Dyfed, UK). The coil was held tangentially to the skull with the handle pointing backward and laterally at a 45 deg angle to the sagittal plane. Electrical mixed nerve stimulation was performed with an electric stimulator (model D7AH, Digitimer, Welwyn Garden City, UK) using a standard stimulation block (cathode proximal) at a stimulation width of 200 μs.

Recording

Electromyographic activity was recorded from the abductor pollicis brevis (APB) muscle using Ag–AgCl surface electrodes (Fischer Medizintechnik, Nurnberg, Germany), with the active electrode mounted on the muscle belly and the inactive electrode placed over the base of the metacarpophalangeal joint of the thumb. Raw signals were amplified using a model 1902 amplifier (Cambridge Electronic Design, Cambridge, UK) and bandpass filtered between 1 Hz and 2 kHz. EMG signals were digitized at 5 kHz by an A/D converter (model 1401 plus, Cambridge Electronic Design) and stored in a laboratory computer for display and later analysis.

Experimental procedures

Measurements were made in each pair with a difference of no more than two hours and between 10.00 h and 16.00 h, to minimize possible circadian influences, in a quiet room at 21–22°C. None of the twins performed any vigorous activity or consumed alcohol and caffeine during the 24 h prior to the tests and all were informed of the importance of having adequate sleep, during the night preceding the tests.

Subjects were seated comfortably in an armchair. At first the optimal site of the magnetic coil for eliciting motor evoked potentials (MEPs) in the resting APB was assessed over the motor cortex at a moderately suprathreshold stimulation intensity (usually 50% of the maximal stimulator output) and marked directly on the scalp with a soft tip pen. At the optimal site (hot spot), the resting motor threshold (RMT) was determined as the minimum stimulation intensity needed to produce a response of at least 50 μV in the relaxed APB in at least 5 out of 10 consecutive trials of the maximal stimulator output (Rossini et al. 1994). Thereafter, the stimulus sufficient to evoke a peak amplitude of 1 mV of the motor evoked potentials in the relaxed APB was determined (SI1mV). SI1mV was 1.3 ± 0.1 times the resting motor threshold. Taking all experiments into consideration, SI1mV was 53 ± 9% of the maximal stimulator output. This procedure took ∼15 min to complete.

For intervention, a paired associative stimulation (PAS) protocol, the principles of which were described previously (Stefan et al. 2000; Wolters et al. 2003; Classen et al. 2004), was employed. This consisted of low frequency (0.1 Hz), repetitive application of single afferent electrical stimuli delivered to the median nerve at the level of the wrist at 300% of the perceptual threshold, paired with single pulse transcranial magnetic stimulation (TMS) at ∼1.2–1.3 times RMT delivered to the hot spot at a fixed interstimulus interval (ISI) of 25 ms. An ISI of 25 ms was used because this interval has been shown in previous experiments to be effective in inducing cortical plasticity in a high percentage of subjects (Stefan et al. 2000).

PAS-induced changes of corticospinal excitability were fully expressed in some studies (Stefan et al. 2000) while in others (Morgante et al. 2006; Weise et al. 2006), with subtly different protocols, maximal increase was noted only after a delay of some 20 min. To account for this effect and to ensure the ability to test for intrapair differences at the full expression of PAS-induced plasticity, corticospinal excitability was monitored for 30 min following the intervention. One hundred and eighty pairs were delivered at 0.1 Hz over 30 min. For amplitudes of MEPs of the resting muscle, 60 trials were collected before and 180 after intervention, using a stimulus intensity of SI1mV and a stimulation rate of 0.1 Hz. Identical stimulus intensities were used before and after intervention (Fig. 1). Throughout the experiment, complete muscle relaxation was continuously monitored by visual and auditory feedback.

Figure 1. Experimental design.

Figure 1

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Test amplitudes were elicited by single-pulse TMS before and after the intervention. During interventional stimulation, 180 pairs of stimuli consisting of electrical stimuli delivered to the median nerve followed by TMS over the optimal site for activating the APB muscle were applied using a constant interstimulus interval and an interpair interval of 0.1 Hz.

The reliability of the measurements on MEPs was assessed in 17 female subjects (5 DZ, 2 MZ pairs and 1 DZ triplet) in a pilot study on two separate days with a week time interval, and was measured using an intraclass correlation analysis of variance (ANOVA) design. Intraclass reliability for the whole sample was found to be 0.75 (P = 0.01), which is in agreement with previous studies (Kamen, 2004). No differences in correlation coefficient were found between MZ and DZ twins (0.73 and 0.77, respectively).

Data analysis

MEPs were measured peak to peak in each individual trial. Changes in the average of MEP amplitudes between each epoch were compared by analysis of variance (ANOVA). A generalized linear model with Bonferroni correction was used to account for the number of multiple comparisons being performed simultaneously. In the current study design, P values would be required to be smaller than 0.0083 to declare significance. To assess the genetic variation on plasticity in human motor cortex, for each subject the average of the MEP amplitudes before the intervention were subtracted from the average of the MEP amplitudes, on the grounds that we did not observe any relationship between the initial pre-interventional values and the change (post-pre interventional values).

Heritability estimates

Heritability (h2), which denotes the degree to which individual differences in a given variable are attributed to genetic differences, was estimated on the basis of the intrapair difference between MZ and DZ twins. MZ twins are genetically identical, whereas DZ twins, like ordinary siblings, share only 50% of their segregating genes. In this way it is possible to separate the relative contribution of genotype and environment for the observed differences in plasticity of human motor cortex. A single-factor analysis of variance (ANOVA) was done to determine the significance of the differences between the mean monozygotic and dizygotic intrapair variance, taking into consideration genetic type and pair factor. The variance ratio (F) derived from the single-factor ANOVA determined whether further analysis was necessary. The following Clark equation based on intrapair variance was used to estimate heritability: Inline graphic, where Inline graphic is the variance of intrapair differences in DZ twins and Inline graphic is the variance of intrapair differences in MZ twins (Klissouras et al. 2007). The computation of h2 was carried out, provided that the difference in genetic variance (within groups mean square) between the twin types (F test) was significant and the difference between means (t′ test) and total variance (within plus between groups mean square) of both types of twins (F′ test), which shows the homogeneity of the sample, was non-significant (Christian, 1979). In this way it was assured that plasticity is independent of the type of twin. Given our total sample size of n = 32 it appears that with type I error probability at 0.05, and the smallest expected difference between MZ and DZ set at h2 = 0.50 a power level of at least 95% was secured in this analysis (Dixon & Massey, 1985).

Results

Characteristics of the subjects

Only modest non-significant differences in age, weight, height and physical activity profiles were seen between MZ and DZ twins (22.6 ± 2.7 and 23.8 ± 3.6 years, 55.8 ± 6.5 and 60.5 ± 11.3 kg, and 164.9 ± 4.6 and 167.5 ± 6.2 cm for MZ and DZ, respectively). Physical activity was also similar within pairs, as well as between zygosity groups. Intra-pair differences were present in menstrual cycle (duration, timing and flow), but were similar in MZ and DZ pairs (data not shown).

Taking all experiments into consideration, resting motor threshold was 41.2 ± 6.7% (mean ± s.d.), stimulus intensity was 53.1 ± 9% of the maximal stimulator output, perceptual threshold of electrical stimuli was 2.6 ± 0.5 mA and intensity of the electrical stimulation was 7.8 ± 1.6 mA. For all these parameters as well as for attention during the experiments, no statistically significant differences were present between zygosity groups (Table 1).

Table 1.

Characteristics of stimulation in monozygotic and dizygotic twins

MZ (18) DZ (14)
Resting motor threshold (%) 40.1 ± 7.4  42.3 ± 7.8
Stimulus intensity (%) 53.6 ± 10.0 52.5 ± 8.7
Peripheral threshold (mA) 2.5 ± 0.5  2.7 ± 0.6
Electrical stimulation intensity (mA) 7.7 ± 1.7  7.9 ± 1.4
Attention (number of errors) 2.6 ± 0.5  2.8 ± 0.6
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Effect of paired associative stimulation (PAS)

Following PAS, the amplitudes of MEP responses recorded from APB muscle increased. The increase amounted, from a mean of 0.99 ± 0.39 mV to 1.21 ± 0.57 mV or on average, of 22% (P = 0.04) 5 min after the intervention, and to 1.42 ± 0.75 mV or of 43% (P = 0.0002) when the measurement was taken 25–30 min after the intervention, consistent with previous observations using a similar protocol (Weise et al. 2006). The percentage increase varied between subjects and ranged from +9 to +210% of the baseline value. In about two-thirds of all experimental sessions the increase was at least 30%.

The build-up of the change in the resting amplitudes was examined by delivering probing TMS pulses for a period of 30 min following the intervention. Resting amplitudes following intervention were binned in epochs of duration 5 min. Including the pre-interventional epoch consisting of 60 consecutive trials, this resulted in seven epochs (one before and six after intervention). A repeated measures ANOVA was performed on the binned data and revealed a significant effect for epoch (0–6) (F = 5.9, P = 0.001). Pre-planned contrasts were computed using Student's t test with the Bonferroni correction to account for the number of multiple comparisons being performed simultaneously. Compared with the pre-interventional measurement, the mean MEP amplitudes at the first five post-interventional epochs were higher, but the results after Bonferroni correction did not reach statistical significance. In contrast, significant differences were identified between pre-interventional and the last (25–30 min) post-interventional epoch (P = 0.007; Fig. 2).

Figure 2. Motor evoked potential amplitudes.

Figure 2

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Average data (means and s.d.) from the resting amplitude increase, in the APB, for all subjects. Significant difference after Bonferroni correction was found only when the pre-interventional was tested against the last post-interventional epoch (paired t test; with the P value estimated at 0.007).

Genetic variation

For the derivation of heritability index, analysis of variance was made in the last post-interventional epoch which remained significant after the Bonferroni correction.

The comparison within any pair showed a greater similarity of the individual profile in plasticity in MZ as compared with DZ pairs. MEP amplitudes were averaged for pre- and post-interventional values for all MZ and DZ twins. Intrapair differences between MZ and DZ twins calculated either from values obtained at 25–30 min after intervention, or on values obtained at 25–30 min after subtraction of pre-intervention values, were almost double for DZ twins in comparison to MZ (0.64 for MZ and 1.25 for DZ, P = 0.036, and 0.42 for MZ and 0.85 for DZ, respectively, P = 0.04). Figure 3 displays intrapair differences in MEP size for MZ and DZ twins, 25–30 min post-intervention after subtraction of pre-intervention values. Differences in DZ twins become more apparent in Fig. 4, where values for monozygous twins are closer to the line of identity, while those for DZ twins are widely scattered for both 25–30 min post-intervention, and 25–30 min post-intervention after subtraction of pre-intervention values. The lower variability in MZ twins can be seen over the whole time course as smaller standard deviations (Fig. 5).

Figure 3. Intrapair differences (mean and s.d.) for motor evoked potential amplitudes in MZ and DZ twins, 25–30 min post-intervention after subtraction of pre-interventional values.

Figure 3

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Asterisk indicates significant difference (paired t test; *P = 0.05).

Figure 4. Individual values of motor evoked potential amplitudes in MZ and DZ twin pairs, 25–30 min post-intervention (upper graph) and after subtraction of pre-interventional values (lower graph).

Figure 4

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BDNF allelic state is also indicated for some twin pairs, of whom 3 DZ and 2 MZ pairs are Val/Val carriers (v/v), 1 MZ pair Val/Met (v/m) and 1 MZ pair Met/Met (m/m).

Figure 5. Intrapair differences (mean and s.d.) for motor evoked potential amplitudes over the whole time course for DZ and MZ twins.

Figure 5

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Previous studies have found the allelic state of the BDNF gene to influence the outcome of PAS (Cheeran et al. 2008). By definition, MZ twins share the polymorphism of BDNF while this is not necessarily true for DZ twins. Hence it is possible that the closer intrapair differences found for MZ twins may be in part due to the same allelic state of BDNF, while the wider intrapair differences for DZ twins may have been due to a different allelic state of BDNF. To address this possibility, the allelic state of 14 twins (4 MZ and 3 DZ pairs) from our total sample was examined using the method applied by Neves-Pereira et al. (2002). Of these twins, 10 were Val/Val carriers (3 DZ and 2 MZ pairs), 2 Val/Met (1 MZ pair) and 2 Met/Met (1 MZ pair). In subjects who carried met in one or more alleles (n = 4), PAS led to virtually no enhancement of excitability from a mean of 0.67 ± 0.41, to 0.68 ± 0.52 or on average a 1% increase. In contrast, excitability was enhanced in those having Val/Val alleles (n = 10) from a mean of 1.05 ± 0.31 mV to 1.72 ± 0.82 mV, an increase of 67% (P = 0.007). Sisters of the same pair had always the same allelic state in all pairs with known BDNF allelic state, even in heterozygous twins (Fig. 4).

For the derivation of heritability index in the plasticity of human motor cortex, ANOVA was employed using the difference of the absolute values between post- and pre-intervention values in order to compare the absolute change of cortical excitability and to determine the significance of the differences between the mean monozygotic and dizygotic intrapair variance, taking into consideration genetic type and pair factor. While the differences between means and total variance of both types of twins were not statistically significant, the genetic variance between the twin types was significant (F = 3.32, P = 0.05). Therefore computation of h2 was carried out in which genetic factors explained 68% of the total variance (Table 2).

Table 2.

Testing statistical hypotheses for the derivation of h2 in plasticity of motor cortex

Hypotheses Plasticity of brain's motor cortex
t′ test 0.83 (0.1 t′ < tc)
F′ test 3.1 (12.3 and 16.1 F′ < Fc)
F test 3.32*, *P < 0.05
Heritability (h2) 0.68
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t′ test signifies the difference between the means of the twin pairs, F′ test the difference of total variance of both types of twins, and F test the difference in genetic variance between the twin types, tc, the subscript denotes the critical value, fc, the subscript denotes the critical value.

Discussion

To our knowledge, this study is the first to use a twin study design to investigate the extent to which individual variation in cortical plasticity is influenced by genetic and environmental factors. The comparison between MZ and DZ twins in plasticity of human motor cortex, which was defined as the change in corticospinal excitability after PAS intervention, demonstrated that externally induced plasticity is in a substantial part (68%) genetically dependent.

A number of other factors that contribute to the observed variation in the plasticity of motor cortex, such as the subject's age (Müller-Dahlhaus et al. 2008), the time of the day (Sale et al. 2008) and the menstrual cycle (Inghilleri et al. 2004) were excluded as underlying the observed differences between monozygotic and heterozygotic twins. Female twins were not matched for phase of menstrual cycle, but since monozygotic twins do not seem to have the same menstrual cycle (duration, timing and flow), intra-pair differences in monozygotic twins were similar to those in heterozygotic twins. Thus, an influence of the menstrual cycle on PAS variability is highly unlikely, and in any case, if this factor had influenced our results, the heritability estimate would be underestimated, because it will lower the MZ resemblance and increase it in DZ twins.

Recent studies in human brain have shown that a single nucleotide polymorphism, BDNF val66met, may be associated with reduced hippocampus volume and episodic memory (Egan et al. 2003; Pezawas et al. 2004), modulation of training-dependent increases in the amplitude of motor-evoked potentials and motor map reorganization (Kleim et al. 2006) and influencing synaptic long-term potentiation and motor learning (Fritsch et al. 2010). Training-dependent increases of excitability (Kleim et al. 2006) or motor performance increments (Fritsch et al. 2010) were reduced in healthy subjects with a val66met polymorphism in the BDNF gene, as compared to subjects without the polymorphism. Extending these studies, Cheeran and colleagues (2008) investigated whether the susceptibility to TMS-induced plasticity is significantly influenced by the BDNF polymorphism. The response of Met allele carriers differed significantly in all protocols compared with the response of Val/Val individuals, suggesting that this was due to the effect of BNDF on the susceptibility of synapses to undergo LTP/LTD. In our subgroup of 14 subjects in whom we were able to ascertain the BDNF gene polymorphisms, we identified four individuals who carried at least one Met allele. PAS-induced response in these four subjects was virtually absent, whereas the remaining subjects carrying the Val/Val allelic state responded with a significant increase. Our observations confirm those of Cheeran and co-workers (2008) who found a significant increase of the MEP amplitudes in APB after PAS in Val/Val, but no increase in non-Val/Val, individuals exposed to plasticity inducing brain stimulation protocols. Based on the assumption that Met alleles would occur at the same frequency as in the cohort of 14 subjects, two DZ pairs could be heterozygous for BDNF gene alleles. Given the large difference in responsiveness toward the PAS protocol in non-Met and Met carriers, it is possible that the BDNF polymorphism may have substantially contributed to the wider intrapair difference for DZ twins. It should be noted, however, that BDNF gene polymorphism is only one example of genetic susceptibility. Polymorphisms of other genes whose product is involved in synaptic plasticity, such as the ‘kidney and brain protein’ KIBRA (Papassotiropoulos et al. 2006) or catechol-O-methyltransferase (COMT) (Jacobsen et al. 2010), could be of similar or even greater relevance. Hence, more studies are needed to determine which gene polymorphisms may underline the difference between MZ and DZ twins.

A recent twin study has demonstrated a major influence of genes on cortical excitability in humans, with heritability estimates of 0.80 for intracortical inhibition and 0.92 for facilitation (Pellicciari et al. 2009). Importantly the same study did not demonstrate a main genetic influence on variation of the size of MEPs evoked by single-pulse TMS, in agreement with our findings in pilot experiments demonstrating similar intra-pair variation of baseline excitability in monozygotic twins. Animal studies show that GABAergic intracortical inhibition powerfully modulates synaptic efficacy (Hess et al. 1996). Furthermore, intracortical disinhibition is known to be involved in PAS-induced plasticity (Stefan et al. 2002). Therefore, greater intra-pair similarity of intracortical excitability in monozygotic twins may have contributed to enhanced intra-pair similarity of PAS-induced plasticity. This mechanism would indicate a less direct influence of genes involved in regulating synaptic efficacy.

The heritability estimate of corticomotor plasticity found in the present study (0.68) was lower than the heritability estimates of Pellicciari and co-workers (2009) relating to intracortical excitability measures. The lower degree of heritability estimates of plasticity may suggests that some additional, non-genetic factors contribute to plasticity variation in genetically identical humans. Such variation could be attributable to environmental and epigenetic (Fraga et al. 2005; Wang et al. 2005) influences. Thus external and internal factors may also affect to some extent the plasticity of motor cortex by altering the pattern of epigenetic modifications, thereby modulating individually genetic information.

PAS-induced facilitation was maximal at the time interval of 25–30 min where it reached 43%, in agreement with previous observations (Weise et al. 2006; Morgante et al. 2006). This pattern of progressive increase in MEP size possibly suggests that there is a latent interval until the optimal strengthening of the synaptic efficacy is consolidated and becomes apparent. Although there was an increment in MEP size comparative to baseline in all post-intervention epochs, after Bonferroni correction only the increment in the last measurement (25–30 min) reached statistical significance with the intrapair differences between MZ being significant less than DZ twins. It could be postulated that both the difference in the degree of MEP amplitude, as well as in the amount of the intrapair differences, during this testing period may be due to a different rate of the increase in excitability. If this were the case, probably a functional mechanism would lead to physiological limits for the particular environmental influence and hence to full expression of an individual's genetic potential.

Our findings, along with those demonstrating a major influence of genes on cortical excitability in humans (Pellicciari et al. 2009), underline the importance of genetic contributions to physiological measures. Therefore, it could be of relevance to include genetic variation as a potential covariate in the analysis of experimental data. As noted above, plasticity induced by paired associative stimulation may probe long-term potentiation of excitatory synapses in motor cortex (Müller-Dahlhaus et al. 2010), a mechanism strongly implicated in motor learning (Rioult-Pedotti et al. 2000). Therefore, it appears tempting to speculate that the same genetic variation that modulates the PAS response could influence motor learning. In agreement with this hypothesis recent evidence obtained in both humans and animals indicates that LTP formation and motor learning are both affected by the BDNF val66met polymorphism (Fritsch et al. 2010). Moreover, it may be that athletes of Olympic calibre in addition to their superior genotypes may also have inherited to some degree the cortical ability to better respond to motor training.

Finally, our findings may also be relevant to understanding why people express different adaptive central nervous system response patterns to various injuries. Functional deficiencies and recovery outcomes differ widely between patients with identical peripheral injuries (Kapreli et al. 2007) possibly as a result of different expressions of central motor plasticity. The fact that heredity accounts for a substantial part of the existing differences in plasticity of human motor cortex, in conjuction with the implication that movement strategies, which are organized in the CNS, are strongly genetically dependent (Missitzi et al. 2004), may also suggest that this influence is a factor in the development of or compensation of certain neurological injuries.

Acknowledgments

The authors thank Professor Dr George Vagenas for advice in statistical analysis, Dr Vassilis Kouvelas for the zygosity determination, Angeliki Misitzi for assistance in genotyping, as well as the twins for their enthusiastic participation in the study. The experiments were supported by the Hellenic Ministry of Education via the Heraclitus Program and General Secretariat for Research and Technology.

Glossary

Abbreviations

APB

abductor pollicis brevis

BDNF

brain derived neurotrophic factor

DZ

dizygotic

ISI

interstimulus interval

LTP

long term potentiation

MEP

motor evoked potential

MZ

monozygotic

PAS

paired associative stimulation

RMT

resting motor threshold

TMS

transcranial magnetic stimulation

Author contributions

J.M.: conception and design, acquisition of data, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content. R.G.: acquisition of data, analysis and interpretation of data, drafting the article. N.G.: analysis and interpretation of data, drafting the article, revising it critically for important intellectual content. P.P.: analysis and interpretation of data, drafting the article. N.K.: analysis and interpretation of data, revising the manuscript critically for important intellectual content. J.C.: conception and design, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content. V.K.: conception and design, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content. All authors approved the final version to be published. The experiments were done in The Human Cortical Physiology and Motor Control Laboratory, Department of Neurology, University of Würzburg, Würzburg, Germany; Ergophysiology Research Laboratory, Department of Sport Medicine and Biology of Physical Activity, University of Athens, Athens, Greece; Section of Histology, Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens, Greece.

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