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J Physiol. Feb 15, 2009; 587(Pt 4): 725–726.
PMCID: PMC2669965

Interhemispheric inhibition between primary motor cortices: what have we learned?

The corpus callosum is the largest white matter structure in the brain that connects homologous cortical areas of the two cerebral hemispheres and plays a critical role in transfer of sensory, cognitive and motor information. Throughout the years much has been learned about hemispheric specialization in the visual system, in language and memory, and in other areas of cognition (Gazzaniga, 2005). Evaluation of interhemispheric transmission times across the corpus callosum in the motor domain relied initially on the analysis of reaction time studies in classical work by Poffenberger (1912). Later on, the analysis of spread of seizure activity from one hemisphere to the other provided more accurate information in patients with epilepsy. There was, however, a gap in knowledge in our ability to characterize the physiological strength of these connections in healthy behaving humans.

Ferbert et al. (1992), following pioneering studies by Cracco et al. (1989) using electrical stimulation, published in The Journal of Physiology the first extensive study that revealed powerful interhemispheric interactions between primary motor cortices (M1) in intact human subjects using transcranial magnetic stimulation (TMS). In this elegant study two magnetic stimulators were used to investigate the effect of a supra-threshold conditioning stimulus over one M1 on the size of a test motor evoked potential (MEP) elicited by stimulation of the opposite M1. The authors observed inhibition of the test MEP at conditioning–test intervals between 6 and 15 ms and even at longer intervals when the conditioning stimulus intensity was increased. A facilitation of the test MEP was observed at times at conditioning–test intervals between 1 and 5 ms. A single suprathreshold TMS pulse was also capable of inhibiting ongoing voluntary EMG activity when applied to the motor cortex ipsilateral to the contracting arm (i.e. ipsilateral silent period). This inhibition lasted for about 30 ms and began 10–15 ms after the minimum corticospinal conduction time to the muscle. The proposed view that both inhibitory interhemispheric effects were mediated through transcallosal pathways was strongly supported by later studies in patients with agenesis of the corpus callosum (Meyer et al. 1995). Direct evidence of the cortical origin of the inhibition induced by the paired pulse technique in later I-waves (I3) was provided by Di Lazzaro et al. (1999) recording descending volleys with epidural electrodes. We have also learned that although the two techniques reflect interhemispheric interactions there are some differences in the time course of the inhibition. For example, by increasing the intensity of the conditioning pulse, the duration of the paired-pulse TMS inhibition increases while the duration of the silent period remained stable. Additionally, interindividual variability in interhemispheric inhibition in proximal arm muscles is higher as measured by the silent period than measured with the paired-pulse protocol. Both inhibitory effects are strong in more distal hand muscles (i.e. first dorsal interosseous). While the exact mechanisms mediating each of these two phenomena remain under investigation, there is tentative consensus on the involvement of transcallosal glutamatergic pathways linking with pyramidal tract neurons through GABAergic interneurons (Reis et al. 2008).

Ferbert et al. emphasized the differences between their finding of predominantly inhibitory interhemispheric effects and results from animal studies in which stimulation of one motor cortex resulted in early contralateral facilitation followed by long lasting inhibition (Asanuma & Okuda, 1962). The absence/inconsistency of the facilitatory effect in Ferbert's report was interpreted as possibly related to masking by surrounding inhibition and/or by the prolonged descending volleys elicited by the test stimulus. An additional difference with animal studies was the strength of the physiological inhibitory effect in human distal hand muscles in apparent contradiction with the evidence of scarce transcallosal connections between distal hand representations in the primary motor cortex (Pappas & Strick, 1981).

The importance of the Ferbert et al. investigation is that it allowed for the first time the evaluation, millisecond by millisecond, of the physiological strength of transcallosal, predominantly inhibitory influences of each M1 on its homologue in the opposite hemisphere. This tool became crucial in subsequent studies of hemispheric specialization in the motor domain and in the evaluation of interhemispheric interactions between different circuits mediating short intracortical inhibition and facilitation in healthy humans (Chen, 2004). More recently, principles similar to those motivating this study were used to evaluate the influence of non-primary motor areas of one hemisphere, like the dorsal and ventral premotor cortex and the supplementary motor area on the M1 of the opposite hemisphere. It is now known that changes in interhemispheric interactions between the M1s are involved in the control of unimanual skilled finger motions in man as well as in the acquisition and transfer of motor skills (Reis et al. 2008).

The technique described by Ferbert et al. was used to evaluate premovement modulation of IHI in patients with stroke. It was found that movements of the paretic hand are accompanied by an abnormally persistent movement-related IHI from the contralesional to the ipsilesional M1 and that the magnitude of this abnormality correlated with the degree of impairment (Murase et al. 2004). Interestingly, measurements of IHI at rest were comparable in stroke patients and controls. Understanding of these abnormalities provided the rationale for testing interventional strategies geared to facilitate excitability in the ipsilesional M1 or down-regulate it in the contralesional M1 in these patients. In this regard, proof of principle studies from different laboratories have shown that the use of non-invasive repetitive TMS that up-regulates excitability within the motor cortex in the lesioned hemisphere or down-regulates excitability in the motor cortex in the intact hemisphere results in some improvements in motor function in patients with stroke (Hummel & Cohen, 2006). The ability to assess interhemispheric interactions between the M1s have provided mechanistic insight into physiological processes underlying motor control in health and disease as well as allowed the hypothesis-driven formulation of interventional strategies to ameliorate motor function after brain lesions, an issue of relevance in clinical neurorehabilitation.

Finally, it is important to keep in mind that the specific mechanisms mediating these different forms of interhemispheric inhibition remain incompletely understood. Acquisition of direct evidence of the specific neurotransmitter systems and neuronal networks involved in this form of intracortical inhibition remains a challenge in our field.

References

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