We used a novel TMS paradigm to evaluate whether the corticospinal responses are abnormally coupled across joints in stroke survivors. Our results indicate that the corticospinal excitability of the quadriceps muscles is differentially modified after stroke. Specifically, stroke survivors exhibited higher excitability of the quadriceps muscles when performing a hip adduction task than during a knee extension task, which was contrary to that observed in the control subjects. This response was consistent in all our subjects indicating that the exaggerated across-joint coupling of the corticospinal responses in stroke survivors is not a random finding.
Following stroke, many subjects often lose the ability to control the muscle groups independently (Brunnstrom, 1970
, Twitchell, 1951
). This loss of independent joint control often results in undesired coupling of joint movements that are inappropriate for the task being performed (Cruz and Dhaher, 2008
, Dewald et al., 1995
, Yao et al., 2009
). The existing evidence suggests that the neural substrates mediating this abnormal coupling may be of cortical origin (Gerachshenko et al., 2008
, Yao et al., 2009
). The cortical representations of the upper-extremity muscles in stroke survivors have been shown to overlap to a much larger extent than control subjects (Yao et al., 2009
). This increased overlap also correlates with abnormal coactivation patterns and across-joint torque coupling in stroke survivors suggesting that abnormal cortical overlap of muscle representation may be one of the underlying mechanisms that mediate post-stroke loss of independent joint control. Data from existing literature also indicate that stroke subjects exhibit abnormal corticospinal excitability of the upper-extremity muscles that are antagonists to the intended movement (Gerachshenko et al., 2008
). This suggests that stroke results in abnormal anatomical or physiological alterations that results in the increased excitability of the non-synergistic muscles that are unnecessary for the intended motion. Our results of abnormal quadriceps muscle excitability during hip adduction than during knee extension, despite controlling for background activation, further support the presence of altered regulation of corticospinal neuronal excitability in stroke survivors. This altered excitability may promote abnormal behavioral responses, which may in turn lead to the formation of atypical movement patterns such as emergence of abnormal muscle synergies during voluntary movements initiated by stroke survivors. We note that, however, there is insufficient data from the current study to determine whether this altered excitability mediates abnormal knee extensor muscle synergy that is commonly observed after stroke. Further investigation is required to systematically verify the existence of a potential causal relationship between the two.
We expected that the quadriceps muscle corticospinal responses of the stroke subjects would be abnormally high during hip adduction in comparison to the control subjects. However, we did not expect that the excitability of the quadriceps muscle corticospinal neurons during hip adduction would be higher than the excitability observed during knee extension (i.e., negative MEP coupling ratios), which is the muscle’s primary direction of action. Our finding of higher corticospinal responses during hip adduction than during knee extension in stroke survivors is a little surprising and counter-intuitive. One possible explanation relates to the differences in the intensity of contractions between the two directions. Due to the well-known effect of background activation on MEP responses (Hess et al., 1986
), we intended to match the background EMG activation of each muscle in both the primary and secondary directions. While we were successful in matching the background activation between the two directions, the contraction intensity at which the subjects performed the two tasks with the same background activity differed. The median contraction intensity for the primary target-matching direction, for instance, was 10% of maximum, whereas to generate similar background activation observed in the primary direction the subjects had to perform target-matching at 30% of maximum in the secondary direction (i.e., target-matching at 30% of MVIC generated in hip adduction produced quadriceps activation values that were similar to those observed during 10% of maximum knee extensor contraction). It seems plausible that the net voluntary effort, rather than background activation, is critical in determining the excitability of the motor cortex. If this is the case, then the MEP coupling ratios should be positive when the effort at which the contractions performed in the two directions are matched for. Indeed, the mean MEP coupling ratios were positive for all the muscles (except stroke vastus medialis) in both groups when the motor evoked responses at similar contraction intensities were compared, yet the between-group differences remained (Stroke MEP coupling ratios: − 0.04 to 0.16, Control MEP coupling ratios: 0.16 to 0.59).
What could be the origin of abnormal coupling of corticospinal responses post-stroke? The exact neural mechanisms underlying this abnormal corticospinal excitability are not clear. Based on the existing evidence, we believe that the plasticity of the brain during the recovery process may underlie this phenomenon. Both animal and human studies suggest that recovery after stroke is associated with axonal sprouting in the cortical and subcortical regions adjacent to the lesion site (Carmichael, 2003
, Carmichael, 2006
, Schaechter et al., 2006
). It is possible that such axonal sprouting could have formed aberrant neuronal interconnections between the proximal and distal muscle groups resulting in coupling of responses between the two. The neuroplastic changes mediated by gamma-aminobutyric acid (GABA) neurotransmitters could be another possible mechanism for the observed coupling of the corticospinal responses (Jacobs and Donoghue, 1991
, Lazar et al., 2010
, Liepert et al., 2000
). Evidence suggests that GABAergic pathways are inhibited after stroke (Liepert et al., 2000
, Manganotti et al., 2002
). Because a reduction in GABA activity promotes expansion of cortical representation and neuronal hyperexcitability through reduced intracortical inhibition, post-stroke inhibition of GABA pathways may have promoted abnormal excitability of adjacent corticospinal neurons, not associated with the intended movement (Jacobs and Donoghue, 1991
, Schiene et al., 1999
). Alternatively, abnormal neuronal activity at the spinal level may have contributed to the observed coupling of the corticospinal responses. There is some evidence to suggest the presence of heteronymous stretch reflex facilitation and reflex mediated coupling of lower-extremity muscles following stroke (Finley et al., 2008
). However, such coupled reflex responses are selectively seen in biarticular rectus femoris; whereas our findings are more global suggesting that changes at the spinal level alone may not fully explain our results. Nevertheless, further experiments are needed to understand the physiological origin of the MEP abnormality in stroke survivors.
The results of this study have potential implications for the way in which noninvasive brain stimulation (NIBS) is applied to promote motor recovery after stroke. There is a growing interest in evaluating the clinical effects of NIBS in stroke population as several studies have shown that NIBS can be effectively used to modulate cortical excitability, enhance motor adaptation and learning, and influence motor memory consolidation (Hunter et al., 2009
, Nitsche and Paulus, 2000
, Pascual-Leone et al., 1998
, Reis et al., 2008
). However, our results suggest that NIBS should be applied with caution, especially when targeting lower-extremity recovery. We speculate that simple application of NIBS, such as repetitive-TMS or transcranial direct current stimulation, to up-regulate or down-regulate the excitability of the cortical hemispheres will result in global modulation. Therefore, it is likely that this global enhancement may also result in enhancement of abnormal across-joint coupling of the corticospinal responses, possibly leading to altered behavioral responses and post-stroke dysfunction. While there is some evidence to suggest that non-invasive brain stimulation may actually decouple abnormal synergistic responses in the upper-limb muscles (McCambridge et al., 2011
), it is currently not clear whether such an effect can be reliably obtained in lower-extremity muscles, especially considering the fact that the spatial resolution of the lower-extremity cortical representation is poor (i.e., isolated targeting of the lower-extremity muscles is very difficult). We are currently working to evaluate the effect of NIBS on abnormal coupling of the corticospinal responses and the best ways to incorporate NIBS as a therapeutic adjuvant to help mitigate post-stroke functional impairments. Until further evidence is available, we recommend that investigators consider that NIBS may promote abnormal across-joint coupling when used as a therapeutic adjuvant for post-stroke lower-extremity neuromotor recovery.
There are some potential limitations in this study. The small sample size of this study limits the ability to generalize our findings to a broader stroke population. However, the observed abnormal MEP coupling ratios were present, albeit in varying levels, in all our stroke subjects irrespective of lesion type and location. This suggests that our findings may be typical in the population of stroke survivors at large. Another concern is that our control group was not age matched to the stroke group. However, there is currently no evidence to suggest that aging induces abnormal neuronal connectivity that would result in altered across-joint torque or corticospinal responses coupling. Indeed, existing evidence indicates that elderly subjects have normal across-joint torque coupling and cortical control mechanisms that suppress unwanted contractions of the muscles that are non-synergistic for the performed action (Cruz and Dhaher, 2008
, Gerachshenko et al., 2008
, Yao et al., 2009
). Moreover, when comparing the data from the young and older adults, it appears that the older subjects behave similar to the younger subjects and showed no signs of abnormal MEP coupling ratios (). Further, we did not find any correlation between subjects’ age and MEP coupling ratio indicating that age was not a confounding factor. Another limitation is that the current study was not designed to evaluate whether the observed alterations in corticospinal excitability contributes to behavioral abnormality in stroke subjects as we controlled for secondary torque generation in our experimental protocol. As a result, it was not possible to characterize how MEP modulation relates to secondary torque generation and whether the abnormal cortical excitability of the quadriceps muscle group is detrimental to function. However, considering the strong evidence related to the presence of abnormal muscle synergy and the associated across-joint coupling in stroke subjects, it appears that this abnormal neuronal excitability may impair functional performance.
In summary, this is the first study to report that quadriceps muscle corticospinal responses are abnormally coupled with hip adductors in chronic stroke survivors. We observed significantly higher excitability of the quadriceps muscle corticospinal neurons during hip adduction than during knee extension in stroke survivors. The across-joint MEP coupling ratios for the quadriceps muscle were also significantly higher for the stroke survivors in comparison to both the young and older subjects. These findings suggest that there is a dysregulation of cortical inhibitory-excitatory regulatory mechanisms, resulting in abnormal excitability of the lower-extremity muscles that are unwanted for a particular intended motor action. Further work is required to elucidate the mechanisms that mediate abnormal coupling of corticospinal responses and to determine whether the altered corticospinal excitability mediates the emergence of abnormal muscle synergies after stroke.