Primary motor cortex
One of the early intriguing findings in the application of TMS to stroke patients was the presence of ipsilateral MEPs within the paretic limb [71
], which are otherwise rarely found in healthy subjects at rest. This also seemed to correlate with other measures of increased excitability in the contralesional M1 [85
]. Interestingly, ipsilateral MEPs have been reported more frequently in poorly recovered stroke patients [71
], a finding interpreted as indicating that contralesional facilitation of excitability may not be a marker of good recovery [80
]. Based on these reports, much interest was triggered regarding to what extent alterations in excitability in contralesional M1 influence recovery of motor function in the paretic arm, and what mechanisms may be involved. In subacute severely paretic stroke patients, Liepert et al reported decreased SICI in contralesional M1 as compared to age-matched controls [88
]; a finding subsequently replicated in more acute patients [36
]. Also, decreases in SICI in ipsilesional M1 have been consistently reported in the literature, both in the acute and chronic periods after stroke [37
]. When assessing changes longitudinally, it does seem that acute disinhibition may, especially contralesionally, normalize over time [92
]. However, how measures of intracortical inhibition or its changes correlate with function at any particular time-point may be highly dependent on initial patient characteristics [36
]. Another issue that is presently under investigation is the extent to which decreased inhibition in contralesional M1 is present in patients with both cortical and subcortical lesions [36
], perhaps explaining the relative variance in reproducibility [94
]. Finally, intense scrutiny is necessary to determine how these electrophysiological abnormalities relate to previously reported abnormalities in metabolic activity of both the ipsilesional and contralesional hemisphere of patients with stroke [97
Beyond investigation of the local changes in excitability of both M1s in stroke patients, it should be kept in mind that functional recovery is likely related to changes in distributed neuronal networks rather than in individual regions. Studies have begun to investigate the alteration in transcallosal neurophysiology after stroke. IHI10
between the two M1s is likely altered after stroke, possibly in a lesion-location dependent manner [105
]. Examining whether changes in IHI10
and SICI after stroke may be related, Butefisch and colleagues have shown that the attenuation of SICI in ipsilesional M1 is not accompanied by a change in resting IHI10
from contralesional to ipsilesional M1. In contrast, disinhibition of contralesional M1 is accompanied but not completely correlated with a decrease in IHI10
from ipsilesional to contralesional M1s [37
]. Together, these findings may imply that at rest, local modulation of inhibition within ipsilesional M1 is prominent. However, a thorough investigation of the resting interactions between SICI and IHI10
, which has begun in healthy individuals [40
], will need to be carried in stroke patients, at various time points and levels of recovery, before more fundamental conclusions can be made. It should also be kept in mind that neurophysiological abnormalities may be more prominent when patients intend to use the paretic hand, rather than when they remain at rest.
Much of these basic cortical physiology measures have been most thoroughly examined at rest. Clearly, extending such measures to active behavior will add significant insight into post-stroke mechanisms of paralysis. For example, the phenomenon of facilitation of M1 excitability by forceful or complex activity of the ipsilateral limb has been explored in the healthy brain [106
]. How modulations in SICI & IHI10
and their interactions may contribute to this facilitation has also been investigated in healthy subjects [106
]. Understanding of these interactions in stroke patients would raise the possibility that non-paretic limb activity could change the physiology of the ipsilesional M1, as proposed in neurorehabilitative interventions like bilateral arm training [112
] or mirror therapy [113
]. However, with isometric force production, non-paretic arm activity in stroke patients does not lead to as much ipsilateral M1 facilitation as seen in healthy controls [114
]. Perhaps this lack of task-dependent modulation in ipsilesional M1 is due to abnormalities in IHI10
after stroke [116
]. Studies have begun to address this question by looking at premovement IHI10
. In chronic, relatively well recovered stroke patients, initially normal levels of IHI10
from the contralesional to the ipsilesional M1 remain abnormally deep at the onset of paretic hand movement, in contrast to the disinhibition that accompanies non-paretic hand movement and movement in age matched controls [117
] during a simple reaction time task ().
Intra- and inter-hemispheric excitability within M1 in the healthy (A) and stroke affected (B) brain
Expanding this line of research to encompass measures of both local and transcallosal neurophysiology and apply them to different motor tasks will allow us to more broadly characterize the neurophysiologic underpinnings of motor deficits after stroke. Clearly, more work is required to fully elaborate these findings.
Non-primary motor regions
Understanding that recovery processes are likely to rely on changes in neurophysiological interactions between different nodes in distributed networks led to the investigations of specific interregional interactions. Investigation of premotor cortex contributions to stroke recovery using TMS have revealed a role for both ipsilesional [119
] and contralesional [103
] dorsal premotor cortices to the functioning of the paretic hand after stroke, with a trend towards contralesional PMd contributing more effectively in patients with more marked impairment, while ipsilesional PMd could be more active in patients with lesser impairment. A prominent possibility for translation of these findings will be investigations into how purposeful modulation of premotor cortical excitability may influence functional recovery after stroke.
It should be kept in mind that identification of neurophysiological abnormalities in patients with stroke is not an easy task. There are technical challenges, as well as a marked heterogeneity in patients’ characteristics that makes generalizations risky. For these reasons, careful manipulation of the various technical tools available is of the utmost importance. It is expected that these new investigations, many presently under way, will in the future allow greater generalizability by fleshing out the details regarding each technique and each subgroup of patients to which they are applied.