Abstract

Performance of unimanual movements is associated with bihemispheric activity in the motor cortex in old adults. However, the causal functional role of the ipsilateral MC (iMC) for motor control is still not completely known. Here, the behavioral consequences of interference of the iMC during training of a complex motor skill were tested. Healthy old (58–85 years) and young volunteers (22–35 years) were tested in a double-blind, cross-over, sham-controlled design. Participants attended 2 different study arms with either cathodal transcranial direct current stimulation (ctDCS) or sham concurrent with training. Motor performance was evaluated before, during, 90 min, and 24 h after training. During training, a reduced slope of performance with ctDCS relative to sham was observed in old compared with young (F = 5.8, P = 0.02), with a decrease of correctly rehearsed sequences, an effect that was evident even after 2 consecutive retraining periods without intervention. Furthermore, the older the subject, the more prominent was the disruptive effect of ctDCS (R2 = 0.50, P = 0.01). These data provide direct evidence for a causal functional link between the iMC and motor skill acquisition in old subjects pointing toward the concept that the recruitment of iMC in old is an adaptive process in response to age-related declines in motor functions.

Introduction

During healthy aging, the brain experiences complex morphological and biochemical changes, including a decrease in white and gray matter integrity (Resnick et al. 2003; Madden et al. 2004; Salat et al. 2004), decline in spine density, changes in synaptic connectivity (Anderson and Rutledge 1996; Burke and Barnes 2006), and a decrease in the availability and the level of several neurotransmitters (Bartus et al. 1982; Kaasinen and Rinne 2002). These neurodegenerative changes are probably the cause of the impairment in a number of cognitive and motor functions during the normal process of aging in humans (Houx and Jolles 1993; Cabeza et al. 1997; Smith et al. 1999).

Functional neuroimaging studies started to investigate the underlying cortical changes across lifespan using a variety of motor tasks of varying complexity (Sailer et al. 2000; Hutchinson et al. 2002; Ward and Frackowiak 2003; Heuninckx et al. 2005; Naccarato et al. 2006; Riecker et al. 2006; Talelli et al. 2008). In general, older adults exhibit enhanced bilateral sensorimotor activation during the execution of unimanual motor activities compared with young subjects, even when behavioral performance was matched (Hutchinson et al. 2002; Mattay et al. 2002; Wu and Hallett 2005). An association between widespread bilateral activation with motor performance has been proposed in old subjects (Mattay et al. 2002; Naccarato et al. 2006), supporting the view that an adaptable and plastic sensorimotor cortical network is able to compensate for an age-related decline in motor function (Sailer et al. 2000; Naccarato et al. 2006; Talelli et al. 2008). So far, however, this assumption was mainly addressed by neuroimaging studies using an indirect associative approach. In fact, it cannot be ruled out that the overactivation observed in the older brain represents a nonselective cortical recruitment, rather reflecting decreased distinctiveness of motor representations for a certain task without functional relevance according to the recently proposed “dedifferentiation theory in the motor system” (see Riecker et al. 2006; Carp et al. 2011; Seidler et al. 2011).

To further disentangle the abovementioned controversy, lesioning experiments (such as cooling or coagulation in animal models) would provide clear information about the functional role of ipsilateral cortical structures for unimanual motor task implementation. In humans, the introduction of noninvasive cortical stimulation techniques, such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS), provide a powerful means to modulate the function of specific neural structures (Siebner and Rothwell 2003). Interference approaches refer, in this context, to reversible functional disturbances of defined brain areas to test their functional relevance for a certain task (Siebner and Rothwell 2003; Hummel and Cohen 2005; Hallett 2007; Nitsche et al. 2008). Thus, in the present study, we investigated the functional relevance of the ipsilateral MC (iMC) for training of a motor skill in healthy old subjects using an interference approach. For this purpose, cathodal tDCS (ctDCS) has been employed in a double-blind, cross-over, sham-controlled design to noninvasively modulate cortical excitability (inhibitory) and perturb the training period of the proposed motor task (Nitsche et al. 2008; Rothwell, 2010).

Methods

Subjects

Twenty-three healthy subjects were divided into groups of young (6 women, 4 men; age range = 22–35 years, mean age = 27 years) and older subjects (7 women, 6 men; age range = 58–85 years, mean age = 69 years). All participants were right handed, as assessed by the Edinburgh handedness inventory (Oldfield 1971). None reported a history of serious medical, neurological, or psychiatric diseases or any contraindications for tDCS or TMS, as probed by a standardized questionnaire, none of them were taking any CNS-active medication and the Mini-Mental State Examination (MMSE) (Folstein et al. 1975) was ≥29/30. Subjects were naïve to the experimental purpose, and none of them were professional piano players or trained as a typist. The study design was approved by the local institutional ethics committee. All participants gave their written informed consent according to the ethical declaration of Helsinki (http://www.wma.net/en/30publications/10policies/b3/).

Motor Task and Study Design

The task employed in the current study is a well-established finger-tapping task that engages activity in a distributed motor network (Karni et al. 1995; Hummel et al. 2003; Walker et al. 2003). It consists of sequential pressing of 5 key strokes (e.g., 3-5-2-4-2) on a 4-button electronic keyboard with the right hand. The fingers were numbered as follows: little finger = 5; ring finger = 4; middle finger = 3; index finger = 2. In each of the study arms (cross-over design, at least 10 days of break interval), 2 different motor sequences with similar degree of complexity confirmed by the Kolmogorov index were tested in a pseudorandomized order (Lempel and Ziv 1976; Hummel et al. 2003). During the study, subjects were comfortably seated in front of a 20-inch screen monitor; the distance between chair and keyboard was kept constant during the study. In a first step, subjects were familiarized with the sequence by reproducing the sequence 3 times in a row without errors. Immediately after being tested on baseline performance, the subjects underwent a first training session (train-tDCS). Ninety minutes and 24 h later, 2 post-training sessions (retrain-90 and retrain-24) followed by a test block (test-90 and test-24) were performed (Fig. 1B). The present design allowed to determine the slope of improvement within the train-tDCS session for both intervention conditions (ctDCS or sham) and to evaluate the potential impact of train-tDCS on the 2 consecutive follow-up sessions without stimulation (retrain-90 and retrain-24). A subset of 5 old subjects was additionally tested 60 days after training for the determination of long-term retention (test-60).

Figure 1.

(A) Schematic representation of a model in which bilateral motor activation was observed in old subjects during the performance of unimanual motor acts (Ward and Frackowiak 2003). (B) Experimental setup. Subjects attended a training session (train-tDCS) composed of 5 blocks each 3 min long with 2 min break in between. Ninety minutes (post-90) and 24 h (post-24) later, a retraining composed of 4 blocks followed by a test block were performed. Cathodal tDCS or sham was applied in a double-blind cross-over design during train-tDCS. VAS-Questionnaires (Q1–6) in which patients characterized (self-report on visual analog scales) level of attention and fatigue were given after baseline and in every session (Table 1). (C) Subjects were seated in an armchair. The motor task consisted of a rapid pressing of 5 sequential keystrokes (e.g., 3-5-2-4-2) on a keyboard. The picture illustrates the position of the tDCS electrodes with the cathode placed over the ipsilateral MC.

Figure 1.

(A) Schematic representation of a model in which bilateral motor activation was observed in old subjects during the performance of unimanual motor acts (Ward and Frackowiak 2003). (B) Experimental setup. Subjects attended a training session (train-tDCS) composed of 5 blocks each 3 min long with 2 min break in between. Ninety minutes (post-90) and 24 h (post-24) later, a retraining composed of 4 blocks followed by a test block were performed. Cathodal tDCS or sham was applied in a double-blind cross-over design during train-tDCS. VAS-Questionnaires (Q1–6) in which patients characterized (self-report on visual analog scales) level of attention and fatigue were given after baseline and in every session (Table 1). (C) Subjects were seated in an armchair. The motor task consisted of a rapid pressing of 5 sequential keystrokes (e.g., 3-5-2-4-2) on a keyboard. The picture illustrates the position of the tDCS electrodes with the cathode placed over the ipsilateral MC.

The subjects executed the sequences as precisely and quickly as possible during each 3-min block, according to the written instruction “Play as many accurate sequences as possible for a trial period of 3 min” (Karni et al. 1998). No feedback was given during the task. The primary outcome measure was the number of correct sequences achieved per block. Additionally, subjects characterized their level of attention toward the task, the perception of fatigue, and the level of pain or discomfort during the stimulation using visual analog scale questionnaires (VAS).

Transcranial Direct Current Stimulation

During the train-tDCS session, ctDCS or sham stimulation was delivered through 2 electrodes covered with a saline-soaked sponge; the surface area of each electrode was 25 cm2 (Eldith, DC-stimulator, Neuroconn, Germany). The cathode was positioned over the projection of the hand knob area of the primary motor cortex of the right hemisphere on the subject's scalp, whereas the anode was placed on the contralateral supraorbital region (Nitsche et al. 2008) (Fig. 1C). The motor cortex representation of the right hand was identified using single pulse TMS (70-mm figure-eight coil, Magstim, Dyfed, UK) following standardized procedures (Siebner and Rothwell 2003). The current was initially increased in a ramp-like fashion over several seconds (8 s) until reaching 1 mA (current density of 0.04 mA/cm2) as described previously (Hummel et al. 2005; Gandiga et al. 2006; Nitsche et al. 2008; Rothwell 2010). tDCS was applied for a total of 20 min. During sham, it was started ramp-like as during real tDCS and faded slowly out after 30 s, a procedure demonstrated to warrant successful blinding (Gandiga et al. 2006; Nitsche et al. 2008). After the completion of train-tDCS, participants were explicitly asked to identify whether they had received “real” or “sham” stimulation.

Data Acquisition and Analysis

Motor performance was recorded with a 4-button electronic keyboard connected to a personal computer using Presentation software (version 0.61, Neurobehavioral System, Albany, CA, USA). For offline analysis, we utilized a custom-made software routine using Matlab (version 7.1.0.246, Copyright 2003, The MathWorks, Natick, MA, USA). Repeated measures ANOVA (ANOVARM) was used: 1) to evaluate the effects of factors AGEyoung,old, INTERVENTIONtDCS,sham, and BLOCKSBaseline-B5 during the train-tDCS session on the number of correct sequences; 2) to analyze the level of attention toward the task, perception of fatigue, and discomfort/pain with the factors INTERVENTIONtDCS, Sham and VAS-TIME. Slopes of improvement were calculated by contrasting the last block of train-tDCS (block-5) and baseline performance. The relation between age and the effects of cathodal tDCS on train-tDCS was analyzed by computing Pearson's 2-tailed correlation coefficient. As we only found significant effects of intervention during the training period in old, we decided to analyze separately the retention and retrain periods for old and young (test-90 and test-24) participants. Nonparametric Wilcoxon test was used to evaluate the effect of INTERVENTIONtDCS, Sham on performance in the 5 old subjects re-evaluated after 2 months (test-60). Normal distribution of the outcome was assessed by Kolmogorov–Smirnov test. All calculations with ANOVARM were Greenhouse-Geisser corrected; post hoc testing was corrected for multiple comparisons by using Student's t-tests if necessary. The level of significance was set at P < 0.05. All statistical analyses were conducted with SPSS 15.0 (SPSS for windows 15.0, Chicago, IL: SPSS, 2006).

Results

All subjects completed the study and none of them reported any adverse effects with ctDCS. Correct number of sequences and psychophysical data in old and in young participants were normally distributed as evaluated by Kolmogorov–Smirnov goodness-of-fit test. There was no difference in pain or discomfort perception between sham and tDCS in old (T[12] = 0.43 P = 0.67) and young participants (T[9] = 0.64 P = 0.53). The type of stimulation did also not influence attention or fatigue (for details, see Table 1). Moreover, neither old nor young subjects were able to distinguish between ctDCS and sham.

Table 1

Attention and fatigue

 sham
 
tDCS
 
Statistics 
Q1 Q2 Q3 Q4 Q5 Q6 Q1 Q2 Q3 Q4 Q5 Q6 ANOVARM 
Old subjects 
 Attention (1–10) 6.0 ± 0.4 6.6 ± 0.4 6.2 ± 0.4 7.6 ± 0.9 7.2 ± 0.8 6.8 ± 0.5 7.3 ± 0.4 6.6 ± 0.7 7.1 ± 0.8 6.4 ± 0.5 7.2 ± 0.3 7.6 ± 0.6 ns 
 Fatigue (1–10) 2.3 ± 0.8 3.1 ± 0.7 2.7 ± 0.6 3.0 ± 0.5 2.4 ± 0.6 2.4 ± 0.6 3.8 ± 0.4 4.0 ± 0.4 3.2 ± 0.8 4.9 ± 0.7 1.8 ± 0.6 2.7 ± 0.7 ns 
 Hand fatigue (1–10) 2.6 ± 0.8 3.2 ± 0.7 2.9 ± 0.8 3.8 ± 0.9 1.6 ± 0.8 2.8 ± 0.7 1.0 ± 0.7 3.4 ± 1.1 1.2 ± 0.8 3.4 ± 0.7 1.6 ± 0.7 3.4 ± 1.2 ns 
Young subjects 
 Attention (1–10) 8.1 ± 0.8 7.9 ± 0.7 8.2 ± 0.6 7.8 ± 0.8 8.1 ± 0.8 7.7 ± 0.7 7.7 ± 0.8 7.5 ± 0.7 7.9 ± 0.8 7.7 ± 0.8 8.1 ± 0.8 7.8 ± 0.7 ns 
 Fatigue (1–10) 1.9 ± 0.8 2.2 ± 0.7 2.3 ± 0.8 2.5 ± 0.8 2.2 ± 0.8 2.1 ± 0.5 2.3 ± 0.8 1.8 ± 0.8 1.8 ± 0.7 1.9 ± 0.7 2.2 ± 0.6 1.9 ± 0.6 ns 
 Hand fatigue (1–10) 0.9 ± 0.6 2.1 ± 0.8 1.8 ± 0.7 1.3 ± 0.6 1.7 ± 0.5 2.2 ± 0.8 1.2 ± 0.7 1.9 ± 0.8 1.3 ± 0.5 1.6 ± 0.8 1.9 ± 0.6 2.1 ± 0.8 ns 
 sham
 
tDCS
 
Statistics 
Q1 Q2 Q3 Q4 Q5 Q6 Q1 Q2 Q3 Q4 Q5 Q6 ANOVARM 
Old subjects 
 Attention (1–10) 6.0 ± 0.4 6.6 ± 0.4 6.2 ± 0.4 7.6 ± 0.9 7.2 ± 0.8 6.8 ± 0.5 7.3 ± 0.4 6.6 ± 0.7 7.1 ± 0.8 6.4 ± 0.5 7.2 ± 0.3 7.6 ± 0.6 ns 
 Fatigue (1–10) 2.3 ± 0.8 3.1 ± 0.7 2.7 ± 0.6 3.0 ± 0.5 2.4 ± 0.6 2.4 ± 0.6 3.8 ± 0.4 4.0 ± 0.4 3.2 ± 0.8 4.9 ± 0.7 1.8 ± 0.6 2.7 ± 0.7 ns 
 Hand fatigue (1–10) 2.6 ± 0.8 3.2 ± 0.7 2.9 ± 0.8 3.8 ± 0.9 1.6 ± 0.8 2.8 ± 0.7 1.0 ± 0.7 3.4 ± 1.1 1.2 ± 0.8 3.4 ± 0.7 1.6 ± 0.7 3.4 ± 1.2 ns 
Young subjects 
 Attention (1–10) 8.1 ± 0.8 7.9 ± 0.7 8.2 ± 0.6 7.8 ± 0.8 8.1 ± 0.8 7.7 ± 0.7 7.7 ± 0.8 7.5 ± 0.7 7.9 ± 0.8 7.7 ± 0.8 8.1 ± 0.8 7.8 ± 0.7 ns 
 Fatigue (1–10) 1.9 ± 0.8 2.2 ± 0.7 2.3 ± 0.8 2.5 ± 0.8 2.2 ± 0.8 2.1 ± 0.5 2.3 ± 0.8 1.8 ± 0.8 1.8 ± 0.7 1.9 ± 0.7 2.2 ± 0.6 1.9 ± 0.6 ns 
 Hand fatigue (1–10) 0.9 ± 0.6 2.1 ± 0.8 1.8 ± 0.7 1.3 ± 0.6 1.7 ± 0.5 2.2 ± 0.8 1.2 ± 0.7 1.9 ± 0.8 1.3 ± 0.5 1.6 ± 0.8 1.9 ± 0.6 2.1 ± 0.8 ns 

Note: Attention and fatigue were assessed with VAS-questionnaire (see timing of questionnaires in Fig. 1, Q1–6). Attention scale: 0–10; 0 = no attention, 10 = highest level of attention. Fatigue scale: 0–10; 0 = no fatigue, 10 = highest level of fatigue. Hand fatigue scale: 0–10; 0 = no hand fatigue, 10 = highest level of hand fatigue. All values were expressed at mean ± SE. ns, not significant.

Carry Over Effects (Baseline Comparison)

Comparable performance levels in terms of correct sequences were observed for the 2 experimental arms in young (basetDCS = 84.7 ± 7.1, basesham = 89.8 ± 9.8; T[9] = 0.7, P = 0.48) and old (basetDCS = 74.3 ± 10.6, basesham = 72.1 ± 10.7; T[12] = −0.4 P = 0.62). Additionally, the order of sequence (Seq-A vs. Seq-B) did not have any impact on baseline performance, in young (base1st = 83.1 ± 8.6, base2nd = 90.2 ± 8.4; T[9] = −1.2 P = 0.25) or old (base1st = 71.3 ± 10.7, base2nd = 75.1 ± 10.8; T[12] = −0.8 P = 0.4), consistent with the absence of relevant carry over effects between experimental arms.

Effects of Intervention on the Train-tDCS Session

ANOVARM revealed a significant main effect of factor AGEyoung,old (F1,21 = 3.9, P = .05) and BLOCKSBaseline-B5 (F5,105 = 19.7, P < .01), without a main effect of INTERVENTIONtDCS,sham in all participants (F1,21 = 3.1, P = .09). Notably, there was a significant triple interaction of AGEyoung,old × BLOCKSBaseline-B5× INTERVENTIONtDCS,sham (F5,105 = 3.7, P = .02) in correct sequences, indicating that the number of correct sequences declined with ctDCS in the old group, post hoc testing revealed that, relative to the sham condition, ctDCS disrupted significantly the second, third, and fifth block of the train-tDCS session.

No other interaction reached level of significance (BLOCKSBaseline-B5× INTERVENTIONtDCS,shamF5,105 = 0.9, P = .4).

The analysis of the slope of improvement revealed a significant difference between young and old with a significant INTERVENTIONtDCS,sham by AGEyoung,old (F1,21 = 5.8, P = 0.02) interaction. Post hoc testing showed that relative to sham, ctDCS induced a shallower slope in old (slopetDCS = −3.2 ± 3.7, slopesham = 16.5 ± 6.8; T[12] = 2.2 P = 0.04), this effect was absent in young subjects (slopetDCS = 30.2 ± 3.6, slopesham = 20.3 ± 5.1; T[9] = 1.3 P = 0.23, Fig. 2B). Important to note, the tDCS-induced effect was independent of the individual baseline performance level as determined by a correlation analysis between baseline performance and tDCS-induced decline (R2 = 0.10, P = 0.29).

Figure 2.

(A) Training under cathodal tDCS led to a consistent decrease in the number of correct sequences in old subjects but not in young participants compared with sham. (B) The bar graphs show the significantly different slope (primary outcome) with cathodal tDCS in old adults, an effect that was not observed in young controls. Error bars indicate SEs (*P < 0.05).

Figure 2.

(A) Training under cathodal tDCS led to a consistent decrease in the number of correct sequences in old subjects but not in young participants compared with sham. (B) The bar graphs show the significantly different slope (primary outcome) with cathodal tDCS in old adults, an effect that was not observed in young controls. Error bars indicate SEs (*P < 0.05).

Additionally, we performed a subgroup analysis in which we selected pairs of old and young subjects according to initial baseline (n = 5, oldsham = 81.4 ± 5.9 vs. youngsham = 81.8 ± 12.7, T[4] = −0.2, P = 0.9; oldtDCS = 84.8 ± 7.4 vs. youngtDCS = 76.6 ± 12.6, T[4] = 0.5, P > 0.6) to further address the question whether the performance at baseline might explain the present results. The analysis of baseline matched subjects showed comparable effects of ctDCS with a strong trend on the interaction of the factors AGEyoung,old by BLOCKSBaseline-B5 by INTERVENTIONtDCS,sham (F5,40 = 2.8, P = .08), supporting the view that baseline performance cannot solely explain the present findings in old subjects.

Association Between Age- and tDCS-Related Effects

A correlation was performed for the ctDCS disrupting effect (operationalized by the ratio of the number of correct sequences during the train-tDCS period under ctDCS divided by the number of correct sequences during sham) and age. Within this analysis, we tested whether the ctDCS effect is dependent on the individual age of the participants. This analysis revealed a significant negative correlation (R2 = 0.24 P = 0.02) indicating that the older the subjects were the more pronounced was the disrupting effect of ctDCS on skill acquisition over the whole group of participants (Fig. 3). As we expected clustering of the data from young and old due to performance differences, the same analysis was performed in the subgroup of old alone revealing an even stronger negative correlation between age and the ctDCS-induced effects (R2 = 0.50 P < 0.01; Fig. 3).

Figure 3.

Relationship between age and the disruptive effect of cathodal tDCS on training. In this linear regression, we observed that age of the participants was negatively correlated with the ratio of correct sequences during tDCS and sham (R2 = 0.24, P < 0.02). It is of note that this correlative effect is even more pronounced in old subjects as demonstrated in the inlay (R2 = 0.50, P < 0.01). These data indicate that the older the subjects were the larger the disrupting effect of cathodal tDCS applied to the ipsilateral MC. The y-axis displays the number of correct sequences with tDCS relative to sham during training with “tDCS < sham” indicating a performance impairing effect of ctDCS.

Figure 3.

Relationship between age and the disruptive effect of cathodal tDCS on training. In this linear regression, we observed that age of the participants was negatively correlated with the ratio of correct sequences during tDCS and sham (R2 = 0.24, P < 0.02). It is of note that this correlative effect is even more pronounced in old subjects as demonstrated in the inlay (R2 = 0.50, P < 0.01). These data indicate that the older the subjects were the larger the disrupting effect of cathodal tDCS applied to the ipsilateral MC. The y-axis displays the number of correct sequences with tDCS relative to sham during training with “tDCS < sham” indicating a performance impairing effect of ctDCS.

Effects of Intervention on Retention

The analysis of the retest blocks in the follow-up periods, revealed a significant difference in correct sequences between both conditions in old subjects for test-90 (test-90tDCS = 83.6 ± 10.1, test-90sham = 96.1 ± 9.2; T[12] = 2.4 P = 0.02) and test-24 (test-24tDCS = 87.9 ± 11.3, test-24sham = 98.4 ± 10.5; T[12] = 2.3 P = 0.03). It is of note that the same analysis performed in young controls did not demonstrate any difference at test-90 (test-90tDCS = 113.4 ± 8.7, test-90Sham = 115.2 ± 14.7; T[9] = 0.1 P = 0.8) nor at test-24 (test-24tDCS = 129.7 ± 11.3, test-24Sham = 127.3 ± 11.4; T[9] = −0.4 P = 0.6; for details, see Fig. 4). The long-term follow-up of a subset of 5 old subjects revealed no effect of INTERVENTIONtDCS,sham on correct sequences at test-60 (Wilcoxon test Z[4] = 0.81, P = 0.41).

Figure 4.

Correct sequences in the follow-up periods for (A) old subjects and (B) young controls. Note: the persistent significant difference in the performance level with cathodal tDCS compared with sham, even after 2 consecutive retraining sessions at post-90 and post-24. Error bars indicate SEs (*P < 0.05).

Figure 4.

Correct sequences in the follow-up periods for (A) old subjects and (B) young controls. Note: the persistent significant difference in the performance level with cathodal tDCS compared with sham, even after 2 consecutive retraining sessions at post-90 and post-24. Error bars indicate SEs (*P < 0.05).

Effects of Intervention on Retrain Periods

Comparing the slope of performance improvement between ctDCS and the sham condition in old subjects revealed no significant differences at post-90 (slopetDCS = 3.8 ± 4.2, slopesham = 4.9 ± 4.1; T[12] = 0.2, P > 0.05) and at post-24 (slopetDCS = 3.4 ± 5, slopesham = 4.6 ± 3.2; T[12] = 0.2, P > 0.05). In the young controls, the slope comparison was also not different at post-90 (slopetDCS = 8.6 ± 6.2, slopesham = 1.9 ± 6.9; T[9] = −0.6, P > 0.05) or at post-24 (slopetDCS = 6.4 ± 8.5, slopesham = 4.2 ± 3.9; T[9] = −0.9, P > 0.05) between ctDCS and sham.

Effects of Intervention on Offline Periods

The analysis of the slope of improvement during 90-min and 24-h break (by contrasting the first block from the following retrain session and the last block from the previous session) revealed no differences in offline learning in old subjects at post-90 (offlinetDCS = 8.2 ± 4.8, offlinesham = 2.9 ± 5.3; T[12] = −0.9, P > 0.05) and at post-24 (offlinetDCS = 0.8 ± 4.5, offlinesham = −2.3 ± 5.1; T[12] = −0.4, P > 0.05). The same offline analysis performed in young controls was also not different at post-90 (offlinetDCS = 5.1 ± 3.7, offlinesham = 6.1 ± 2.3; T[9] = −0.4, P > 0.05) or at post-24 (offlinetDCS = 12.4 ± 7.9, offlinesham = 8.1 ± 6.8; T[9] = 0.3, P > 0.05).

Discussion

The present study evaluated the functional relevance of the iMC during the training of a unimanual motor skill in young and old healthy adults. The main findings were 1) that cathodal tDCS applied to the iMC led to an impairment of training with a decrease of correctly played sequences in old subjects, 2) the magnitude of the disruptive effect was more prominent the older the subjects were, and 3) even after 2 consecutive retraining sessions without stimulation (retrain-90 and retrain-24), the performance level achieved with sham was still not yet accomplished within the ctDCS condition. These findings support the view of a causal relation between the disruption of function of the iMC and motor skill acquisition. By this, the data strongly support the concept that the iMC is involved in the implementation and acquisition of complex unimanual motor behavior in healthy old individuals, but not in young, as suggested in previous neuroimaging studies (Mattay et al. 2002; Naccarato et al. 2006).

During healthy aging, several motor abilities decline (Smith et al. 1999; Seidler et al. 2002). Aging-related deterioration of motor function (e.g., slowing of movements, loss of accuracy, and impaired fine motor skills) results in functional disabilities in healthy old humans affecting daily life activities, independence, and quality of life (Giampaoli et al. 1999). Nevertheless, a number of healthy old subjects maintain a high level of performance until very old age. Thus, it has been hypothesized that neural redundancy allows the brain to undergo neuroplastic changes during healthy aging to remodel sensorimotor networks to keep function at best levels (Rossini et al. 2007; Park and Reuter-Lorenz 2009). In this context, neuronal plasticity might be the basis for adaptation to age-related functional deficits to maintain cognitive and motor capabilities to fully function in everyday life (Burke and Barnes 2006; Rossini et al. 2007).

In the cognitive domain, Cabeza (2002) proposed the model of Hemispheric Asymmetry Reduction in Older Adults, describing the finding that older adults demonstrate decreased prefrontal cortex lateralization across different tasks (Cabeza 2002). Similarly, when performing a unimanual motor task, older adults exhibit bilateral over-recruitment relative to young adults, with increased engagement of the MC ipsilateral to the moving hand (Ward and Frackowiak 2003; Heuninckx et al. 2005; Riecker et al. 2006). Based on these findings, it has been hypothesized that the additional activation of these motor cortical areas refers to plastic reorganization to compensate for degeneration and decline in motor function and to optimize motor output (Mattay et al. 2002; Ward and Frackowiak 2003; Naccarato et al. 2006). Interestingly, the magnitude of the additional recruitment is most likely task-specific and especially related to the difficulty/complexity of the motor task (Heuninckx et al. 2008). Although not mutually exclusive from compensation, the possibility remains that this engagement of additional motor cortical areas in the old might represent nonselective or functionally irrelevant coactivation (Riecker et al. 2006; Carp et al. 2011). Even detrimental effects of enhanced bilateral activation has been recently suggested, Langan et al. (2010) found that older adults that successfully inhibited (less activation) the iMC showed faster reaction times (Langan et al. 2010).

As a matter of principle, neuroimaging studies with EEG, MEG, PET, or fMRI are based on the analysis of associations between concomitant modulation of behavioral and neurophysiological parameters such as electric fields, metabolic, or blood-flow changes; they are not geared at testing causality between local brain function and behavioral output. The latter is the domain of inactivation techniques such as the Wada test or, noninvasively, temporary interference approaches with TMS or tDCS as used in the present study (for review, see Hummel and Cohen 2005; Fregni and Pascual-Leone 2007; Hallett 2007; Nitsche et al. 2008). Therefore, our findings in the present study favor a model in which ipsilateral motor areas are suggested to be functionally recruited in old adults as an adaptive response to aging processes, a relevant mechanism not only involved in the control of movements but also in the acquisition of new motor skills.

Noninvasive brain stimulation techniques are increasingly used to investigate human cognitive and motor functions in both healthy individuals and neurological patients (Wassermann et al. 2008; Schulz et al. 2013). Strikingly, a different scenario, compared with the findings in old, appears to be present in patients with chronic stroke, where a virtual lesion/interference of the contralesional MC (ipsilateral to the moving paretic hand) suggested that persisting contralesional activity might be, at least in part of the patients, the result of maladaptive reorganizational processes (Hummel and Cohen 2006; Zimerman et al. 2012). The present data suggest that neuroplastic changes leading to reorganization in the ipsilateral (to the moving/paretic hand) MC after stroke and during healthy aging might have a clearly different functional role, rather adaptive during normal aging but possibly maladaptative in patients with chronic stroke. This view is still somewhat speculative but provides a reasonable working hypothesis for upcoming studies (Hummel et al. 2008).

Dissecting the skill acquisition process in its temporal components (online, offline) revealed that the main disrupting ctDCS effect determined at follow-up (retention) was mediated mainly through an impairment of online effects in the old participants. Of note, we did not find any detrimental effect of stimulation in young controls. Based on previous studies, one could have even hypothesized that motor performance might improve with ipsilateral ctDCS in the young (Vines et al. 2006; Kobayashi et al. 2009) due to modulation (reduction) of interhemispheric inhibition from the ipsilateral to the contralateral motor cortex (Plewnia et al. 2003; Schambra et al. 2003). The absence of any changes in young individuals might reflect a ceiling effect, that is, the motor task used in the present study was rather simple and perhaps not challenging enough for young subjects in whom the motor system is so well tuned and robust that the present disrupting protocol did not interfere with behavior.

Interpretation of the present results is constrained by the fact that 25-cm2 sponge electrodes were used to apply ctDCS to the cortical representation of the ipsilateral FDI in the hand knob area. Recent neuroimaging studies showed increased ipsilateral activity in the primary but also in secondary motor and somatosensory areas and subcortical structures in old subjects (Ward and Frackowiak 2003; Ward et al. 2008). Owing to the size of the stimulation electrodes, we cannot rule out that the effects of stimulation are not entirely restricted to the primary MC, but also spread to some extent to adjacent cortical areas like the premotor cortex (Nitsche et al. 2007; Wagner et al. 2007). It is of note to consider that remote effects of noninvasive brain stimulation have been even described in the contralateral motor cortex. However, within the present design, if an effect in the contralateral MC would be anticipated, we would expect a reduction of interhemispheric inhibitory interaction resulting in an enhancement of excitability in the contralateral MC with rather behavioral improvement and not impairment as found here. Although unlikely, we cannot completely rule out behavioral effects of the reference electrode (anode) over the contralateral prefrontal cortex.

In summary, one of the significant problems of the aging population is a general decline in motor functions. A greater understanding of age-related motor system reorganization is an important precursor to design appropriate interventions to support sensorimotor functions. The present findings support the view of an adaptive functional role of the ipsilateral motor cortex for the implementation of motor behavior and the acquisition of motor skills in healthy old subjects to keep performance at best levels.

Funding

This research was supported by a grant from the DAAD (German Academic Exchange Service) to M.Z. (A/07/95990), Alexander von Humboldt Foundation (Feodor-Lynen) to F.C.H., the Forschungsförderungsfonds Medizin of the University of Hamburg (NWF-04/07 to F.C.H.; NWF-11/09 to M.Z.) and by the SFB 936 Multi-Site Communication in the Brain (C4 to F.C.H.) of the German Research Foundation.

Notes

Conflict of Interest: None declared.

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