This study aimed to explore the cortical activation changes underlying behavioural improvement evoked by tDCS to the motor cortex in patients with stable, chronic disability after a first stroke. Both within and outside the MRI scanner we found that anodal tDCS applied to ipsilesional M1 improved response times across widely varying levels of recovery, confirming previous behavioural reports in more restricted patient groups (Fregni et al., 2005
; Hummel et al., 2005
For the first time, the immediate functional MRI brain activation changes associated with these behavioural improvements were characterized. Anodal tDCS to ipsilesional M1 was associated with increased task-related activity in the ipsilesional (stimulated) motor cortex, premotor cortex and supplementary motor
area. Moreover, the degree of behavioural improvement immediately following tDCS was correlated with the stimulation-induced changes in functional MRI signal within the stimulated M1. It may be that the mechanisms underlying long-term behavioural improvements in patients are different from those demonstrated here. Repeated, multiple sessions of tDCS potentially lead to longer-lasting motor improvements (Boggio et al., 2007
; Reis et al., 2009
). One previous study using 5 days of motor training paired with a ‘dual’ stimulation montage found evidence for increased motor-related activity in ipsilesional M1 after the 5
day training period (Lindenberg et al., 2010
). Future work should test whether this increased activity is also found for the conventional montage used here.
Both anodal tDCS applied to ipsilesional M1 and cathodal tDCS applied to contralesional M1 were associated with increased ipsilesional M1 activation and in our behavioural study both were associated with some degree of performance improvement, although for cathodal tDCS this improvement was only seen when contrasted with the sham tDCS session. When the regions of increased motor-related activity after anodal tDCS to ipsilesional M1 and cathodal tDCS to contralesional M1 were directly compared a region of overlap was demonstrated within the hand region of ipsilesional M1, highlighting this region as a possible anatomical substrate for the behavioural improvement seen in response to stimulation. However, univariate analyses of functional MRI data cannot easily provide insights into network hierarchies. Future studies using effective connectivity analysis (Marreiros et al., 2008
) or using complementary modalities that provide greater temporal resolution, such as magnetoencephalography, could be used for this purpose.
It has been previously shown that anodal tDCS increases excitability within the stimulated region (Nitsche et al., 2000
) and, in addition to glutamatergic effects, decreases the total γ-aminobutyric acid (GABA) pool within the stimulated region (Nitsche et al., 2005
; Stagg et al., 2009a
). As well as increases in glutamatergic signalling, decreases in GABA-ergic activity have been implicated in behavioural improvements in rodent models of stroke (Clarkson et al., 2010
). Future pharmacological studies could test whether GABA modulation is a critical mediator for the behavioural effects observed here, possibly explaining the smaller magnitude of the behavioural effects of cathodal tDCS applied to contralesional M1.
An earlier, smaller study previously had suggested possible behavioural improvements in patients following strokes after cathodal tDCS applied to contralesional M1 (Fregni et al., 2005
). We partially replicated this observation in Experiment 1, but found that the behavioural effects of cathodal tDCS to contralesional M1 were much weaker than those of anodal tDCS to ipsilesional M1, as cathodal tDCS to contralesional M1 led to no absolute improvement in response times but did lead to a reduction of the increase in response times seen with sham tDCS, which we believe is a fatigue effect. Although motor-related brain activity during the simple response time task was increased in ipsilesional M1 with cathodal stimulation, in contrast to our findings for the anodal tDCS condition, no relationship between performance and functional MRI activity was found. The increased activity within the stimulated (contralesional) M1 in response to cathodal tDCS applied to contralesional M1, an inhibitory tDCS protocol, is in line with findings from our previous study in healthy controls (Stagg et al., 2009b
), and, in inhibitory repetitive transcranial magnetic stimulation studies has previously been suggested to be the result of locally decreased synaptic efficiency (Lee et al., 2003
It is not clear why there is a discrepancy between the magnitude of the effects of cathodal tDCS applied to contralesional M1 reported here and in the previous study, where cathodal tDCS applied to contralesional M1 was found to be as effective as anodal tDCS to ipsilesional M1 (Fregni et al., 2005
). It is unlikely that the behavioural probes used in this study are insensitive to the effects of tDCS, as we and others (Hummel et al., 2006
) have demonstrated robust significant effects on a simple response time task of anodal tDCS to ipsilesional M1. A potentially important difference between the current study and the previous work (Fregni et al., 2005
), is that our patient group was more impaired. Increased activity in the contralesional hemisphere may be functionally important rather than maladaptive in more severely impaired patients (Johansen-Berg et al., 2002
; Gerloff et al., 2006
; Lotze et al., 2006
We did not find any significant improvement in grip force following either stimulation condition. A previous study reported improved grip force (and response times) following anodal tDCS to ipsilesional M1 (Hummel et al., 2006
). However, the patients in the current study were more severely impaired than those in previous reports. In our experience, moderately and severely impaired patients find maintaining the optimal posture for good task performance difficult. We did not find any effect of either stimulation condition on choice response time. It may be that the more moderately and severely impaired patients in this study found the wrist extension movement required for this task difficult. It is also possible that this dorsal premotor cortex-dependent choice response time task is not affected by tDCS to M1; even though the electrode position used might be expected to have some effects on at least the more caudal parts of dorsal premotor cortex. An alternative explanation for the effects of tDCS on response times seen is as reflecting a global change in attention, rather than a specific motor effect. We would consider this unlikely as no effect was seen on the choice-response time task and the number of responses excluded due to long reaction times in the simple response time task did not change with stimulation. However, we cannot rule out this possibility. Future studies testing alternative stimulation sites could explore in more detail the anatomical specificity of the effects found here.