Post-lesional cerebral reorganisation: Evidence from functional neuroimaging and transcranial magnetic stimulation

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Abstract

Reorganisation of cerebral representations has been hypothesised to underlie the recovery from ischaemic brain infarction. The mechanisms can be investigated non-invasively in the human brain using functional neuroimaging and transcranial magnetic stimulation (TMS). Functional neuroimaging showed that reorganisation is a dynamic process beginning after stroke manifestation. In the acute stage, the mismatch between a large perfusion deficit and a smaller area with impaired water diffusion signifies the brain tissue that potentially enables recovery subsequent to early reperfusion as in thrombolysis. Single-pulse TMS showed that the integrity of the cortico-spinal tract system was critical for motor recovery within the first four weeks, irrespective of a concomitant affection of the somatosensory system. Follow-up studies over several months revealed that ischaemia results in atrophy of brain tissue adjacent to and of brain areas remote from the infarct lesion. In patients with hemiparetic stroke activation of premotor cortical areas in both cerebral hemispheres was found to underlie recovery of finger movements with the affected hand. Paired-pulse TMS showed regression of perilesional inhibition as well as intracortical disinhibition of the motor cortex contralateral to the infarction as mechanisms related to recovery. Training strategies can employ post-lesional brain plasticity resulting in enhanced perilesional activations and modulation of large-scale bihemispheric circuits.

Introduction

During the past two decades experimental studies in animals, and neurophysiological and neuroimaging studies in humans have demonstrated that the adult brain maintains the ability to reorganise throughout life. Cortical reorganisation or plasticity as defined by Donoghue is “any enduring changes in the cortical properties either morphological or functional” (Donoghue et al., 1996) and of major interest as it may play an important role in learning and functional recovery after injury to the nervous system.

Since the pioneering work of Merzenich and his colleagues (for references see Merzenich and Sameshima, 2000) it is known that the overuse or disuse of limbs lead to an increase or decrease of the corresponding cortical representations, respectively. Motor cortical representations can reorganise rapidly in response to different stimuli, such as peripheral nerve lesions (Donoghue et al., 1990, Sanes et al., 1988), ischaemic nerve block (Brasil-Neto et al., 1993), and in relation to motor performance (Bütefisch et al., 2000, Classen et al., 1998, Nudo et al., 1996).

The pivotal question for restorative neurology of whether such plasticity also operates after cortical damage was approached in specific ablation experiments. For example, Nudo et al., 1996, observed that the cortical finger representations adjacent to partly damaged finger representations became enlarged with rehabilitation, while they remained unchanged in the untreated monkeys. In such experiments evidence was provided showing that reorganisation occurs in the adult nervous system both adjacent to a focal brain damage leading to plastic changes of the representation within the affected system. Furthermore, destruction of areas 1, 2 and 3 in the hand area of primary somatosensory cortex of the monkey (SI) has been shown to lead to an immediate unresponsiveness of the hand representation in SII, the second somatosensory cortex, a functionally related but distinct co-operative area (Pons et al., 1988). More importantly, however, 24 h later the formally unresponsive hand area in SII was occupied by a foot representation. Later it was shown that experimental brain lesions typically induce plastic changes in cortical and subcortical locations also remote from the lesion in related systems (Witte et al., 2000).

The underlying mechanisms involve the unmasking of existing, but latent, horizontal connections (for review Sanes and Donoghue, 2000) or modulation of synaptic efficacy such as long-term potentiation (LTP) (Hess and Donoghue, 1994, Hess et al., 1996) or long-term depression (LTD) (Hess and Donoghue, 1996). The neurotransmitter systems involved in mediating these effects include the inhibitory GABAergic system (Hess et al., 1996, Hess and Donoghue, 1996) as well as the excitatory glutamatergic system with activation of NMDA receptors (Hess et al., 1996).

The availability of non-invasive neuroimaging and electrophysiological techniques allow us today to study reorganisation in vivo in the human brain. The functional neuroimaging techniques include measurements of the regional cerebral blood flow (rCBF), regional cerebral metabolism of glucose or oxygen (rCMRGlu, rCMRO2) and of neuroreceptor and neurotransmitter systems using positron emission tomography (PET) as well as diffusion weighted imaging (DWI) and perfusion imaging (PI) using magnetic resonance imaging (MRI). In addition, rCBF-measurements with PET and measurements of blood oxygen level dependent changes with functional MRI (fMRI) allow mapping the cerebral structures that participate in sensory perception, the execution of an experimental task or in cognitive problem solving. Of interest with respect to this chapter, PET and fMRI have been employed for studying normal brain function including brain plasticity related to learning (see Toga and Mazziotta, 2000). More recently, PET and fMRI have also been used for studying the reorganisation of functional representations in relation to recovery from human brain diseases including cerebral ischaemia. A fundamental problem when studying patients with focal brain lesions or psychiatric disorders, such as psychosis, is that one has to differentiate between the task-specific activation patterns and the disease-related functional changes since the latter may obscure the task-specific activation patterns (Price and Friston, 1999).

Transcranial magnetic stimulation (TMS) provides additional information on processes involved in cerebral reorganisation. Changes of the human cortico-spinal motor output system such as changes of the maps of cortical excitability related to use or injury of the brain can be studied. More recently, paired-pulse TMS has provided means to study intracortical inhibitory and excitatory activity thereby allowing to study the differential regulation of intracortical neuronal networks involved in reorganisation of the brain (Bütefisch et al., 2003, Liepert et al., 2000a). Further, by combining TMS with drugs that either block or enhance TMS evoked responses, neurotransmitter systems mediating the observed effects can be identified (Bütefisch et al., 2000, Stefan et al., 2002, Ziemann et al., 1998; for review Cohen et al., 1998). Also, “artificial reversible brain lesions” can be introduced with repetitive TMS which allow to probe the specific role of a cortical area for a given behavioural task (Hilgetag et al., 2001, Jahanshahi and Rothwell, 2000, Rossi et al., 2001).

In this paper we will show in which way neuroimaging techniques and TMS have enabled us to study cerebral reorganisation after lesions to the central nervous system and, thereby, mechanisms of recovery. This knowledge is a prerequisite to develop neurobiologically based strategies for neurorehabilitative interventions. We will focus on brain infarction for two reasons. First, in the majority of patients, brain infarction is a well defined localised lesion to the brain with a clear temporal onset. In this sense it is comparable to lesion experiments in animals. Second, brain infarction in the territory of the middle cerebral artery territory leading to hemiparesis provides a means to study the lateralised sensorimotor system which allows differentiating perilesional from remote activation related to recovery of arm function.

Section snippets

Functional neuroimaging of acute stroke

In patients with a transient functional impairment as in a transient ischaemic attack, recovery may result from restitution of tissue function after a short-lasting ischaemia or from reorganisation adjacent to a small brain lesion within the remaining functional network. These mechanisms can now be studied in humans with MRI techniques such as perfusion and diffusion weighted imaging (PI, DWI). Interruption of circulation due to cerebral artery occlusion induces immediate changes in cerebral

Evaluation of the motor output system

Transcranial magnetic stimulation (TMS) is a non-invasive technique in which a focused magnetic field pulse is used to evoke an electrical discharge of cortical neurones. If the resulting discharge is of sufficient magnitude, a motor evoked potential (MEP) is measurable in the muscle where the cortical neurones are projecting to (target muscle). The size of the MEP depends on the intensity of the magnetic stimulus, the excitability and number of cortical neurones and on the integrity of the

Synthesis of functional imaging and transcranial magnetic stimulation: perspectives for rehabilitative techniques

As described earlier in this paper, functional neuroimaging can show the brain areas affected by a neurological disease such as ischaemia in stroke. Also, the brain areas activated in relation to a given brain function can be mapped to brain anatomy. Transcranial magnetic stimulation (TMS) provides additional information, since it allows assessing the pathophysiological impact of the abnormal imaging findings: TMS can be used to specifically examine the relation of the neurological deficit to

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