Cortical excitation and inhibition by the corpus callosum

Doty says that very little is known about the neural signals that pass between the hemispheres, and the same could be said of the effects of these signals on their target neurons in the human brain. In the analysis of in-terhemispheric interactions, it is often claimed that one hemisphere may wholly inhibit or facilitate the other hemisphere in a multitude of sensory, motor, and cog-

Giovanni BERLuccHi Dipartimento di Scienze Neurologiche e della Visione, Sezione di Fisiología Umana, Universita di Verona, Verona, Italy.

nitive activities. Apart from the unlikelihood that normal cerebral organization may include such massive and indiscriminate interhemispheric actions, the terms facilitation and inhibition are used in this connection in a very loose sense, simply to mean that a particular behavioral performance that is attributed to one hemisphere appears to be improved or worsened, respectively, when that hemisphere is freed from interhemispheric influences. There is still much confusion about how these gross inhibitory and facilitatory interhemispheric influences inferred from behavior can be related to precise physiological actions of the corpus callosum at the neuronal level. In experimental animals, classic electrophysiologi-cal techniques have succeeded in demonstrating synaptic facilitatory and inhibitory effects of callosal fibers onto single cortical neurons (e.g., Matsunami and Hamada, 1984). At present, the available electrophysiological evidence suggests that all callosal fibers are excitatory to their direct target neurons in the cortex. The presence of exceptional callosal fibers that may be directly inhibitory to their postsynaptic targets is inferred from anatomical findings of very few GABA-immunopositive neurons among the nonpyramidal neurons that project to the corpus callosum. In adult rats, GABA-immuno-positive neurons that are presumed to be inhibitory have been estimated to account for at most 3—5% of callosally projecting neurons (Gonchar, Johnson, and Weinberg, 1995). By contrast, in rat pups 21% of callosal neurons were found to be GABA-positive, and 57% of callosal neurons were found to have an electro-physiologically demonstrable direct inhibitory action on their target neurons (Kimura and Baughman, 1997). Taken together, these findings in adult and fetal or neonatal rats indicate that a transient contingent of callosal inhibitory fibers, whose prenatal and perinatal functions are as yet unknown, is virtually eliminated during post natal development by the process of corpus callosum pruning discovered by Innocenti (1986).

In adult animals, inhibition of cortical neurons by the callosal input is assumed to be indirect insofar as it is predicated on callosal excitation of intracortical inhibitory neurons. As Doty mentioned, the findings of Asa-numa and Okuda (1962) suggest that corticipetal callosal discharges set up highly organized spatial patterns of combined and concurrent excitatory and inhibitory effects in discrete cortical regions, rather than widespread inhibitions or facilitations of large cortical areas or even of an entire hemisphere. As can be expected, direct evidence of synaptic inhibitory and excitatory actions of the corpus callosum in humans is virtually nonexistent, but recent applications of the noninvasive transcranial magnetic stimulation technique for activating the cortex have provided suggestive indirect information. Appropriate magnetic stimulation of the motor cortex on one side produces electromyographic responses in the intrinsic muscles of the contralateral hand; callosal inhibition or excitation of motor cortex can be inferred from changes in the threshold for obtaining such responses as a result of conditioning stimuli applied to the motor cortex of the other side. Although some of these studies have reported that inhibition is the only consistent effect of such transcallosal stimulation (e.g., Ferbert et al., 1992), others have found that inhibition is systematically preceded by excitation (Ugawa, Hanajima, and Kana-zawa, 1993; Salerno and Georgesco, 1996), in agreement with the notion that callosal excitation is monosynaptic while callosal inhibition is polysynaptic. However, the interpretation of these results is made difficult by the possible antidromic activation of callosal neurons, a confounding factor that has plagued the understanding of cortical responses to electrical callosal stimulation since the early electrophysiological experiments in animals. Like most corticofugal neurons, callosal neurons have axons with recurrent collaterals that project to in-tracortical neuronal pools on the side of the parent cell body, thus providing an anatomical basis for positive and negative feedback effects. The participation of antidromic callosal stimulation to cortical effects was first shown by Clare, Landau, and Bishop (1961), who cut the corpus callosum in cats, waited for the anterograde degeneration of callosal fibers, and then recorded surface cortical responses to electrical stimulation of the ipsilateral callosal stump. The evoked responses were remarkably similar to those evoked by electrical stimulation of the intact corpus callosum and such as to suggest that the latter stimulation always evokes nonsynaptic (purely antidromic) and synaptic responses. Clare and colleagues (1961) assumed that synaptic responses to callosal stimulation following anterograde degeneration of callosal fibers must have been mediated via recurrent axonal collaterals of antidromically activated callosal neurons, and their assumption was later confirmed with single-neuron recordings by Feeney and Orem (1971). Although transcranial magnetic stimulation is supposed to act mainly on neurons rather than fibers, the possibility that callosal fibers are directly activated in an antidromic way by such stimulation is by no means excluded (Cracco et al., 1989), and in fact it is indirectly supported by a study of activation of corticospinal neurons by magnetic transcranial stimulation in monkeys (Edgley et al., 1997). In sum, the emphasis on cortical inhibition as a major effect of transcallosal magnetic stimulation in humans may be misplaced if intracortical inhibitory neuronal pools are brought into play via recurrent axonal collaterals of antidromically activated callosal fibers. Thus, transcranial magnetic stimulation may be useful for studying local inhibitory mechanisms in the human cortex (e.g., Meyer et al., 1995; Liepert, Tegenthoff, and Malin, 1996; Schnitzler, Kessler, and Benecke, 1996) but cannot clarify the normal physiological participation of the corpus callosum in such mechanisms unless the contribution of antidromic stimulation to the observed effects can be fully understood and measured.

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