Mechanisms and modulation of plasticity in motor cortex and its implication for recovery after stroke: Studies with transcranial magnetic stimulation

Abstract

The adult brain maintains the ability for plasticity throughout life. The underlying mechanisms are of major interest as plasticity plays an important role in learning and functional recovery after injury to the brain. An important concept derived mainly from stimulation experiments in animals is that of a distributed neuronal network where multiple overlapping motor representations are functionally connected through an extensive horizontal network. By changing the strength of horizontal connections between motor neurons, functionally different neuronal assemblies can form, thereby providing a substrate to construct dynamic motor output zones. Modulation of GABAergic inhibition and synaptic efficacy such as long-term potentiation (LTP) are mechanisms involved. Transcranial magnetic stimulation (TMS) provides means to study changes of the human corticospinal motor output system and intracortical inhibitiory and excitatory networks in response to different stimuli in humans. In combination with drugs that either block or enhance TMS evoked responses, neurotransmitter systems mediating the observed effects can be identified. Using this combined approach we were able to identify NMDA receptor activation and GABAergic inhibition as mechanisms operative in use-dependent plasticity in intact human motor cortex. Further, d-amphetamine, a drug that operates by increasing monoaminergic transmission, enhances this process. Another approach is the application of TMS to motor cortex that is engaged in generating training movements in a Hebbian type paradigm. The important role of GABAergic inhibition was also demonstrated for other forms of plasticity in human motor cortex. Transient deafferentation of the forearm induced by a blood pressure cuff that is inflated above systolic blood pressure across the elbow results in a rapid reduction of GABAergic inhibition and increase of the motor cortical output to muscles proximal to the ischemic block. This approach was applied to patients after stroke. Motor practice of the paretic hand during deafferentation of the upper arm, produced by plexus anaesthesia, improved hand motor function dramatically. In addition to these processes involving intact neuronal tissue of motor cortex in the affected hemisphere, changes in excitability of contralateral homotopic motor cortex has been described. Specifically, the balance of excitatory and inhibitory activity was shifted towards an increase of excitatory activity. This shares similarities to mechanisms implicated as relevant for reorganizational processes after experimental brain injury and may be relevant for functional recovery after stroke.