Contribution of transcranial magnetic stimulation to the understanding of mechanisms of functional recovery after stroke

Motor evoked potentials (MEP)

When TMS is applied at intensities above motor threshold, the activation of excitatory interneurons can result in volleys of upper motor neuron activity which subsequently activate alpha motor neurons of the spinal cord. The summed activity, an MEP, is measured via electromyography (EMG) from surface or needle electrodes over or in the muscles of interest [19], or as descending volleys of direct (D) or indirect (I) waves recorded directly from epidural electrodes over the spinal cord, close to the pyramidal tract [20, 21]. The amplitude, area under the curve, and latency of MEPs are all used in various ways to measure motor cortical excitability.

Resting motor threshold (rMT) is defined as the intensity of stimulation required to produce an MEP of small amplitude in 5 out of 10 trials [19].

Stimulating M1 at different stimulus intensities (relative to rMT intensity or maximum stimulator output) creates an input/output or recruitment curve of MEP amplitudes [22, 23] that is usually sigmoidal in shape. rMT is predominantly influenced by mechanisms of neuronal membrane excitability, evidenced by its alteration in the presence of pharmacological modifiers of sodium and calcium channels and relative stability in the presence of modifiers of synaptic transmission [24-26]. rMT also correlates with measures of white matter microstructure [27]. In contrast, recruitment curves are contributed to by changes in synaptic excitability, as evidenced by their alteration in the presence of pharmacological modifiers of synaptic transmission [23, 28].

Short-interval intra-cortical inhibition (SICI) and facilitation (SICF)

Exploiting TMS’ preferential activation of interneurons and transsynaptic activation of pyramidal tract cells has allowed for a better characterization of inhibitory and facilitatory mechanisms operating within M1. Paired pulse stimulation delivered through the same magnetic coil over M1, where a suprathreshold test stimulus (TS) is preceded by a sub- or supra-threshold conditioning stimulus (CS), can be used to gain insight into the relative contribution of local inhibitory and excitatory inputs to M1 pyramidal tract cells. The CS can cause an increase in MEP amplitude (facilitation, SICF) or decrease in MEP amplitude (inhibition, SICI) compared to the MEP evoked by the TS alone. Inter-stimulus intervals of approximately 1.5-3ms cause attenuation of MEP amplitudes or SICI [29], which seems to be at least partially GABA-A receptor mediated [21, 30-33]. With longer inter-stimulus intervals (~6-10ms) it is possible to observe a facilitation of MEP amplitudes, referred to as SICF [34], a more heterogeneous measurement that may have a significant spinal component [35]. One additional measurement that has been proposed as useful has been the determination of recruitment curves of SICI, a method perhaps underutilized that is likely to call for more attention in the future[36, 37].

Another test of intracortical inhibition is the contralateral cortical silent period (CSP), a drop in background voluntary EMG activity which occurs when a suprathreshold TMS pulse is delivered to the M1 contralateral to a muscle that is voluntarily activated. It has been proposed that the later part of the contralateral CSP [38] is a GABA-B receptor mediated cortical phenomenon [24], and hence likely represents a separate inhibitory network or mechanism within M1 relative to SICI [30].

Inter-hemispheric inhibition (IHI)

The inhibitory interactions between the two M1s can be evaluated using a paired pulse technique [39], where a suprathreshold CS is applied over the conditioning M1 at about 10ms prior to the TS applied to the conditioned M1. While other inter-stimulus intervals have been used, the 10ms interval has been the most widely studied (IHI₁₀). IHI₁₀ is likely mediated via transcallosal glutamatergic neurons from the conditioning M1 interacting with local GABA-B receptor mediated inhibitory interneurons within the target M1 [40, 41]. Another form of measuring interhemispheric inhibition is the ipsilateral CSP, evidenced as the suppression of voluntary EMG activity in one muscle via ipsilateral M1 stimulation [39, 42-44]. While both IHI₁₀ and ipsilateral CSP are forms of transcallosal inhibition, they are likely mediated by different subsets of transcallosal neurons and different interactions with local inhibitory circuits as evidenced by the lack of correlation in input/output curves between the two measures. Also, the current direction of the CS influences the level of ipsilateral CSP induced, unlike IHI₁₀ [44, 45]. While both can be considered complementary measurements, ipsilateral CSP can be especially useful in stroke patients who may not have measurable MEPs in the paretic limb after stimulation of the ipsilesional M1, but can produce voluntary EMG activity. Measures of ipsilateral CSP in the paretic limb can reveal the level of transcallosal inhibition targeting ipsilesional M1 [46].

Inter-regional interactions

Paired pulse and rTMS methods have also been used to evaluate the influence of non-primary motor areas within the same and opposite hemispheres on M1, including dorsal premotor (PMd)[47-53], supplementary motor (SMA)[47, 54], parietal [55], and cerebellar areas [56-60].

Motor mapping

A cortical map of a target muscle’s representation can be rendered by measuring MEP amplitudes evoked in that target muscle by TMS applied to different scalp positions [61-64]; by weighting each point by some measure of the overall map, a center of gravity for a particular muscle representation can also be determined. Motor mapping using TMS has some similarities with mapping using functional neuroimaging in that the size of the map depends to some extent on the intensity of stimulation used and in that an increase in map size may be due to either increased excitability of an unchanged cortical representation or of an actual centrifugal increase in motor map size [65]. Alternatively, motor maps may show well characterized topographic displacement of the center of gravity, as for example what occurs after amputation, where a nearby representation expands consistently over the deafferented representation [66], indicating real representational plasticity.

Central motor conduction (CMC)

The latency of MEP onsets can be used to measure nervous system conduction time. When peripheral conduction time is also known, via magnetic stimulation of the cervical roots or F-wave testing, then a central motor conduction time can be calculated [67, 68]. Abnormalities in central motor conduction time may be due to axonal or demyelinating lesions of the corticospinal tract.

This brief introduction intended to define some of the most common TMS measurements and their proposed mechanisms as they have been applied across healthy volunteers and post-stroke populations. For a more detailed description of these measurements and their impact on motor control, please refer to more thorough reviews [33]. Overall, these techniques allow detailed analysis at various levels of interactions within and across cortical areas in health and disease.

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, 80-84], 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 [85-87]. 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, 89-92]. Also, decreases in SICI in ipsilesional M1 have been consistently reported in the literature, both in the acute and chronic periods after stroke [37, 90, 93-95]. When assessing changes longitudinally, it does seem that acute disinhibition may, especially contralesionally, normalize over time [92, 96]. 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, 92, 96]. 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, 91], perhaps explaining the relative variance in reproducibility [94, 95]. 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 [97-104].

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, 106], 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 [106-111]. 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, 115]. 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, 118] during a simple reaction time task (Figure 1).

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.