Neuromagnetic integrated methods tracking human brain mechanisms of sensorimotor areas ‘plastic’ reorganisation

Brain Research Reviews 33 (2000) 131–154 www.elsevier.com / locate / bres

Full-length review

Neuromagnetic integrated methods tracking human brain mechanisms of sensorimotor areas ‘plastic’ reorganisation a, b P.M. Rossini *, F. Pauri b

a IRCCS S Giovanni di Dio, Istituto Sacro Cuore, Brescia, Italy AFaR –CRCCS Ospedale Fatebenefratelli Isola Tiberina Roma, Italy

Accepted 11 April 2000

Abstract The potential for reorganization in the adult brain has been largely underestimated in the past and we are just beginning to understand the organisational principles involved in functional recovery. A bulk of experimental evidences have been accumulated in support of the hypothesis that neuronal aggregates adjacent to a lesion in the cortical brain areas can be progressively vicarious to the function of the damaged neurones. Such a reorganisation, if occurring in the affected hemisphere of a patient with a monohemispheric lesion, should significantly modify the interhemispheric symmetry of somatotopic organisation of the sensorimotor cortices, both in terms of absolute surfaces and number of ‘‘recruited’’ neurons, as well as of spatial coordinates. In fact, a roughly symmetrical organisation of sensorimotor — particularly for the hand contorl — in the right and left hemisphere has been observed in healthy humans by different methods of functional brain imaging, including fMRI, TMS, MEG, HD-EEG. Not uniform results about the functional brain activity related to sensory, motor and cognitive functions in normal and diseased subjects are often due to differences in the experimental paradigm designed as well as in the spatial and temporal resolution of the neuroimaging techniques used. The multi-modal integration of data obtained with several neuroimaging techniques allowed a coherent modelling of human brain higher functions. Functional magnetic resonance imaging (fMRI) provided fine spatial details (millimetres) of the brain responses, which were compared with the cortical maps of the motor output to different body districts obtained with transcranial magnetic stimulation (TMS). Magnetoencephalography (MEG) ability to study sensorimotor areas by analysing cortical magnetic fields, is also complementary to the motor cortex topographical mapping provided by TMS. MEG high temporal resolution allows to detect relatively restricted functional neuronal pools activated during cerebral processing of external stimuli. Moreover, these brain responses can be investigated with magnetoencephalography (MEG) and high density electroencephalography (EEG) techniques, with elevated time resolution (ms). With respect to the high resolution EEG technique, the MEG technique allowed a more precise localisation of the sites of neural activity buried into the cortical sulci, but was unable to detect the response of the crown of the cortical giri and of the frontal-mesial cortex (including the supplementary motor area), because of its poor sensitivity to radially oriented dipoles. The integration of functional and anatomical information provide cues on the relationship between brain activity and anatomic sites where this takes place, allowing the characterisation of the physiological activity of the cortical brain layers as well as to study the plastic reorganisation of the brain in different pathological conditions following stroke, limb amputation, spinal cord injury, hemisperectomy.  2000 Elsevier Science B.V. All rights reserved. Keywords: Removal reorganization; Rehabilitation; Stroke; Functional recovery; MEG; TMS; fMRI

Contents 1. Introduction ............................................................................................................................................................................................ 2. Physiology .............................................................................................................................................................................................. 2.1. Physiology of motor system ............................................................................................................................................................. 2.2. Physiology of primary somatosensory cortical areas ..........................................................................................................................

132 132 132 133

*Corresponding author. Divisione di Neurologia, Ospedale Fatebenefratelli Isola Tiberina 39-00186 Roma, Italy. Tel.: 139-066-837-300; fax: 139-066-877-448. E-mail address: [email protected] (P.M. Rossini). 0169-328X / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0169-328X( 00 )00090-5

132

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

2.3. Physiology of sensorimotor interaction ............................................................................................................................................. 2.4. Basic mechanism for plastic reorganisation ....................................................................................................................................... 3. Technologies for non-invasive functional brain imaging ............................................................................................................................. 3.1. TMS: basic principles and parameters for measuring sensorimotor brain plasticity ............................................................................... 3.2. MEG: basic principles and parameters for measuring sensorimotor brain plasticity .............................................................................. 4. Experience-dependent and sensory deprivation brain reorganisations tracked via neuromagnetic methods ...................................................... 4.1. Deafness and musicians ................................................................................................................................................................... 4.2. Blindness........................................................................................................................................................................................ 4.3. Motor learning ................................................................................................................................................................................ 5. ‘Peripheral’ and ‘Central’ lesions affecting sensorimotor brain areas functionality. Follow-up of recovery ..................................................... 5.1. Peripheral nerves lesions and limb amputation .................................................................................................................................. 5.2. Spinal cord lesions and motoneuron diseases..................................................................................................................................... 5.3. Monohemispheric brain lesions ........................................................................................................................................................ 6. Conclusion.............................................................................................................................................................................................. Acknowledgements ...................................................................................................................................................................................... References...................................................................................................................................................................................................

1. Introduction In language dictionaries, the terms plastic and plasticity describe something which is pliant, supple or capable of being moulded. This definition implies change in the physical structure, but when we apply it to dynamic and biologic phenomena like such as behaviour or brain function, we have to reconsider this definition in a more careful way. For instance, one of the most important aspects of the plasticity of a body organ (i.e. the brain) is the potential for change which can be explored both during development and maturity by the imposition of transient or stable abnormal circumstances which disrupt the normal condition. One of the most astonishing properties of the mammalian brain is its capacity of adaptation for change, commonly referred to as ‘neural plasticity’. Pioneering studies have repeatedly shown how the brain possesses the ability to reorganise itself after peripheral sensory deprivation, by allowing neighbouring cortical regions to expand into territories normally occupied by the input from the deprived sense organs [29,74,119,10,107,80]. More recently, a bulk of experimental evidences have been accumulated in support of the hypothesis that neuronal aggregates adjacent to a lesion in the sensorimotor brain areas can be progressively vicarious to the function of the damaged neurones [142,18]. Such a reorganisation, if occurring in the affected hemisphere of a patient with a monohemispheric lesion, should significantly modify the interhemispheric symmetry of somatotopic organisation of the sensorimotor cortices, both in terms of absolute surfaces and number of ‘recruited’ neurons, as well as of spatial coordinates. In fact, a roughly symmetrical organisation of sensorimotor areas — particularly for the hand control — in the right and left hemisphere has been observed in healthy humans by different methods of functional brain imaging, including PET, fMRI, TMS and MEG. In this review article, the information gathered via different methods of brain functional imaging, with particular emphasis on neuromagnetic techniques like Magnetoence-

134 134 135 135 135 137 137 137 139 141 141 142 142 149 150 150

phalography (MEG) and Transcranial Magnetic Stimulation (TMS) are reported in different physiological and pathological conditions inducing ‘plastic’ brain reorganization.

2. Physiology Sensory perception and its use in assessing motor plans involves large brain areas including primary somatosensory, visual, motor cortices as well as secondary sensory and motor areas. Basal ganglia and thalamic relays significantly contribute to motor planning, sensory perception and sensorimotor integration. Supplementary motor and premotor cortices have a pivotal role in motor preparation and execution which, on their own, are carried out via corticospinal fibres from primary motor cortex. Cerebellar relays constantly monitor the motor output and motor execution.

2.1. Physiology of motor system The existence of multiple yet discrete efferent microand macrozones from primary motor cortex is now accepted as representative of an essential organisational principle of this area in animal experimental models. Several reports from different research groups have shown that a particular movement can be elicited from selective and direct stimulation of different MI regions, often several millimetres apart, separated by non-responsive districts [89,26,64,125,127,42,46,121,30,47]. This is true both during surface stimulation with single and trains of electric pulses and during intracortical microstimulation, showing that identical movements could be elicited from multiple, non-contiguous sites [47]. The injection of neuronal tracers like Horse Radish Peroxidase has shown dense bi-directional projections, interconnecting areas of the macaque monkey motor cortex for digits, wrist, elbow and shoulder movements, sometimes as distant as 8 millimetres. This observation nicely fits with the classical

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

study by Kwan et al. [64], in which intracortical microstimulation was identifying some segregated areas in MI triggering movements in shoulder, elbow, wrist and fingers. Such a large body of evidence challenges the labelled-line hypothesis, which suggests that the control of the primate arm is like in a robotic hand having with separate software channels, servo amplifiers and motors for each digit; on the other hand, it supports the view that any movement is controlled by a network of neurons distributed throughout the MI cortex (i.e. the whole hand area for individual finger movements). Moreover, such studies provide evidence of (a) convergence of output from large, overlapping cortical territories onto single muscles; (b) divergence of output from any given cortical site to multiple muscles; and (c) extensive horizontal interconnections between subregions within the MI [47]. The existence of extensive pyramidal tract neuron colonies for individual motoneurons, and the ‘aggregation colonies’ [2] projecting to different muscles explains why a considerable amount of overlap for fitting the cortical representation of the entire musculature into the limits of area 4 is mandatory. In particular, Pyramidal Tract Neurons projecting to spinal motoneurons for hand muscles often show adjacent cortical cell clusters, which facilitate different muscles [67]. What is the functional meaning of the motor cortex output map? Why is somatotopic representation in MI so diffuse while other cortical maps — such as SI in which each finger is mapped in an ordered somatotopic arrangement [56,92] — are so precise? Previous theories interpreted motor maps as a simple somatotopic representation of either joint movement or muscles. More recent views consider the multiple representations and overlap of outputs to different motoneurons and muscles; therefore, the lack of a precise and ‘frozen’ somatotopic organisation is encountered both in the motor cortex and the corticospinal tract. In this respect, it seems more than obvious that the large volume of motor cortex devoted to hand and finger movements is due to the huge neural circuitry subserving their extraordinary repertoire of movements. Therefore, multiple representations of an individual muscle can be seen as the substrate for the different combinations of movement strategies in which such a muscle can be involved. The organisation with multiple representations of motor output highlights the co-ordination of action initiated by many muscles at different joints. Local interaction of output modules with different target muscles is allowed thanks to the overlap of contiguous joint representations within the motor cortex [64]. Evidence for such interaction can be obtained by demonstrating synaptic connectivity between cortico-motoneuronal cells with different muscle groups. The functional need for the strict co-ordination of different muscle fields stems from the observation that the stability of the proximal arm and girdle are essential prerequisites for the successful execution of relatively independent finger movements. More-

133

over, the body surface is a two-dimensional sheet, which can be reproduced as a two-dimensional surface in a point-to-point fashion in SI, while movements occur in a three-dimensional space with several degrees of freedom. The idea of co-operative operation of multiple cortical areas is advantageous for functional plasticity; for example, co-operating areas may progressively substitute for the role of a related dysfunctional area, and do so more easily if such a function stems from a distributed neural network more than from a restricted, highly specialised and unique group of cells. In conclusion, multiple representation underlying different motor functions of separate body parts may overlap spatially and temporally [120]. This type of arrangement offers a flexible organisation with evident implications in motor learning and plastic reorganisation, leading to recovery of motor function following a lesion.

2.2. Physiology of primary somatosensory cortical areas It is generally agreed that neurons in parietal area 1 of the primate receive information from slowly adapting receptors, while those in area 3b respond to either slowly or rapidly adapting receptors [56,88,129]. In area 3b, digit representation sites responding to rapidly adapting receptors are grouped into anteriorposteriorly oriented bands that are surrounded by similar districts, in which cells respond to slowly adapting receptors [128]. Powell and Mountcastle [96] showed in the anaesthetised monkeys that neurons in area 3b and 1 differ from those in areas 3a and 2, the latter being predominantly driven by deep receptors (i.e. joint movements). There is experimental evidence of both cutaneous and deep receptors depending upon the position of the examined neuron in the somatotopical representation within area 2 [73,94,93]. For instance, many neurons in the palm and arm districts of area 2 receive deep input, while those within the digit representation almost exclusively receive cutaneous inputs [91]. Such a receptive field /sensory submodality relationship is less evident for areas 3a and 1 and is completely lacking in area 3b where cutaneous input is dominating. Several experimental studies have suggested a sort of roughly separated functional organisation within the different areas of SI; area 2 being more ‘associative’ in function than area 3b which, on its own, extracts quantitative data relative to a stimulus in a given skin locus. On the other hand, cells from areas 1 and 2 would analyse more complex features — such as velocity and the presence of edges — of a stimulus, which crosses different districts of the receptor surface [49]. Post-central, Somatosensory cortex (SI) is a major source of somatosensory input to the motor cortex [54], being as it is also the only primary sensory receiving area to have direct access to MI. Moreover, direct thalamic input is dispatched to M1. Concerning the internal connectivity of SI, it is worth mentioning that: (a) area 3b projects to areas 1 and 2, while

134

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

area 1 is also reciprocally connected with areas 2 and 3b; (b) inputs from deep receptors are selectively projected to areas 3a and 2 as relayed by the anterodorsal shell of VPL thalamic nuclei; (c) the cutaneous input from the central core of VPL is relayed selectively to cortical areas 3b (more densely) and 1 [51–55]. In area 3b, the representation of the glabrous skin of each digit occupies about 1–2 square mm in the primate; digit 1 is more laterally represented, while digit 5 is the most medial one [75].

significantly affect the amplitude of cortico-cortical EPSPs, IPSPs, and reflect the changes of synaptic efficiency. In this respect, it is of paramount importance that the continuous flow of sensory input to MI from subcortical (namely thalamic) and cortical (from SI) relays are coupled to the ‘efferent copies’ of the pending movement which MI delivers in parallel to SI via corollary discharges of cortico-cortical connections. In fact, they represent the framework for a comprehensive sensorimotor integration.

2.4. Basic mechanism for plastic reorganisation 2.3. Physiology of sensorimotor interaction Excitatory as well as inhibitory mechanisms of motor cortical circuitries can be significantly modulated by sensory flow. This effect would have a remarkable importance in favouring or disfacilitating synaptic efficiency mechanisms, which are at the basis of neural reorganisation. In human forearm — hand muscles, it is known that an afferent conditioning input from the same body region where the muscle ‘target’ of the cortical motor output is located provokes an initial decrement of excitability (conditioning-test interval of 10–20 ms), which is followed by a huge increment of responsiveness of the motor cortex to the externally applied TMS (conditioning-test interval of 25–35 ms; [72], [58]). Moreover, by using the pairedpulse techniques (in which two successive TMS are applied to the same scalp site, the 1st being subthreshold, the 2nd frankly suprathreshold for motor response elicitation), it has been shown that at the time of the MEPs facilitation there is also a decrement of intracortical inhibition suggesting that the former is a predominantly cortical mechanism [100]. Meanwhile, the importance of the sensory flow from the hand on the stability of the motor output maps has been recently established in humans [103]. Anaesthetic block of the sensory fibers from the skin enveloping ulnar innervated muscles of the hand induces a significant and transient decrement of the excitable area. At the same time, a trend toward an enlargement in cortical representation of the adjacent muscles was evident [103]. Finger anaesthesia induces short-term changes of finger somatotopy in SI with progressive enlargement of the cortical representation of the unaesthetised fingers [107]. This phenomenon is absent or even reversed whenever an interference (i.e. pain) overlaps with sensory deprivation [13]. Deafferentation or continuous sensory bombardment of cortical relays in SI and MI both induce, therefore, rapid changes in the cerebral cortex, presumably by unmasking of pre-existing connections. It is still a matter of debate as to what extent neuronal sprouting, or the unmasking of existing (functionally silent) synapses from a prevailing inhibition or a biochemical suppression, is involved in the reshaping of motor output during motor learning or following a (‘peripheral’ or ‘central’) lesion. Long Term Potentiation and Inhibition (LTP and LTI; [118]) are basic mechanisms, which

Several mechanisms may contribute to plastic brain reorganisation during sensorimotor learning or following a lesion of sensorimotor brain areas. They include changes in neuronal membrane excitability, removal of local inhibition, and changes in synaptic efficacy (both excitatory and inhibitory). The latter change is probably based upon Na1 or Ca21 channels at least for short-term changes, while LTP-like mechanisms should be invoked together with NMDA receptor activation for long-term changes [145]. Of the several candidate mechanisms for cortical plasticity, persistent changes of synaptic efficacy, as proposed by Hebb on theoretical grounds in 1949 [44], have been favoured by many as underlying learning and memory, as well as some of the cortical plasticity related to acquisition and recovery of sensorimotor function. Ever since it was discovered in the hippocampus, LTP has been regarded as the prototypic mechanism of a modified synaptic efficacy [9]. At least three types of LTP have been described; they include (a) when it occurs at an input to a postsynaptic cell, or (b) when concomitant and synchronous activation of another input to the same cell, or (c) when there is concomitant and synchronous postsynaptic depolarisation [15]. In this way it can be explained how converging inputs from various sources, including corticocortical and thalamocortical connections, could interact leading to a reshaping of cortical input–output somatotopy [8,27,4]. Experience-dependent cortical plasticity usually involves changes of synaptic efficacy, which follows Hebbian rules [44,97,98]. Consequently, peripheral lesions may unmask hidden inputs that normally do not lead to suprathreshold activation of a postsynaptic neuron [34,99]. Competition between neural representation with different activity levels is one of the fundamental principles of cortical plasticity. Competition within a single modality, where neighbourhood relationships are defined on the basis of topography, leads, for instance, to an expansion of the adjacent face region following deafferentation from the hand area. In a competitive system — like such as the sensorimotor areas — deprivation will accelerate the expansion of a competing input / output channel; meanwhile, increased attention or training devoted to this second channel obviously can help as well. Synaptic efficacy and threshold for activation can both be influenced by the temporal structure and synchronisation of impulse arrival and neuronal firing [28,1].

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

3. Technologies for non-invasive functional brain imaging Different types of techniques for investigating functional brain imaging are nowadays available. One group of them measures regional blood flow and metabolic changes linked with function-related changes in neuronal firing level. They include Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI). Another group of techniques analyses electromagnetic properties of the brain neurons, which can be assessed via modern types of ElectroEncephaloGraphy (EEG), MagnetoEncephaloGraphy (MEG) and Transcranial Magnetic Stimulation (TMS). When mapping the motor output from motor cortical areas, PET and fMRI provide a comprehensive view of the distributed network subtending a given motor act, together with a superb, detailed relationship between function and anatomy. Such multiple-representation findings disagree with the classical Penfieldian view which considers that in MI each major body segment — such as the hand / arm district — muscle representation shows in an orderly progression for those acting from proximal to distal joints mapped in a point-to-point fashion onto the anterior– posterior extent of the precentral gyrus. However, there are a number of intrinsic limitations in both the PET and fMRI techniques, that at the present time cannot be eliminated. Amongst others, they include: the length of examined epochs necessary to find out statistically significant activation (from 1 s to min) within which no temporal sequence can be discriminated; the inability to differentiate decrease from increase of neuronal firing in the activated areas (or exciting from inhibiting net effects); and the inability to discriminate the activation directly linked to motor programming and execution from the sensory feed back from the moving parts, and to track any chronological relationship between the activated areas and the types of movement relationships between joints and muscles. Moreover, the hemodynamic response follows the onset of electromagnetic brain activity by a delay of several hundred ms [38]. This clearly limits the ability of blood-flow dependent techniques to investigate temporal sequencing for the activation of different brain areas in a given experimental condition [62].

3.1. TMS: basic principles and parameters for measuring sensorimotor brain plasticity Until relatively recently, non-invasive methods for testing the excitability threshold, as well as the scalp representation of the motor cortex, were not suitable for humans. Starting from the mid-1980s, a safe and painless technique of transcranial brain stimulation (TMS) via brief magnetic pulses has been introduced [5]. In the following years, more focal stimulators able to activate a discrete part of the motor cortex have been progressively introduced and successfully employed both in normals and in patients

135

(see [104], for a review). Since then, the opportunity of defining precise maps of motor output has been developed. Transcranial Magnetic Stimulation is a non-invasive technique which allows painless excitation of the neural structures underlying a stimulating coil, where an extremely brief and intense magnetic field is created by circulating within it a transient, robust electric current [5,106,116]. TMS, when applied on the scalp regions corresponding to the motor strip, trigger transient electromyographic responses in the connected ‘target’ muscles (Motor Evoked Potentials5MEPs; [105]). By means of this method, the threshold of excitability and the propagation properties of the corticospinal fiber contingent governing the ‘target’ muscle(s) can be examined in detail [108,109]. Various types of coil shapes, sizes and orientation allow the preferential excitation of discrete brain regions, so that mapping procedures can be carried out on healthy human beings [22,39,85]. Such mapping procedures have systematically shown a rough somatotopy of the motor output with the leg and shoulder muscles more medially and posteriorly located and the arm and hand muscles more laterally and anteriorly located. Despite an increasing number of stimulation sites allowed to plot progressively more detailed maps, however, the number of ‘target’ muscles from which MEPs were simultaneously recorded for such mapping studies have been always quite limited to usually one or two, up to a maximum of four [141]. Recent studies in our centre using electromyographic recordings from more than ten different upper limb muscles have shown ‘clusters’ or muscle aggregations during focal TMS, together separate hot-spots for different muscles (Fig. 1, manuscript in preparation); this observation is in agreement with the idea of a distributed motor network along the precentral cortical strip of MI. Changes in cortical maps can usually show two main characteristics: (1) enlargment or restriction without changes in the centre of gravity of the excitable area (possibly due to the recruitment or derecruitment of a fringe of neurons adjacent) or (2) migration of the responsive area outside the usual boundaries (possibly due to a lesion affecting the brain district where the hot spot is located). Such a ‘migration’ might be apparent (i.e. better evidence of a secondary hot-spot previously hidden by the predominant one one) or real, following progressive activation of new synaptic connections.

3.2. MEG: basic principles and parameters for measuring sensorimotor brain plasticity Magnetoencephalography (MEG) represents a non-invasive technique able to spatially identify the synchronous firing neurons in restricted cortical areas, in relation to spontaneous cerebral activity or in response to an external stimulus. MEG is blind to the effects of extracerebral layers on the brain’s electromagnetic signals, and preferentially reflects the tangential component of dipoles in the depth of gyri and sulci. MEG follows the spatial

136 P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154 Fig. 1. (A) 3D MRI reconstruction of the brain of one healthy subject undergoing focal TMS mapping during multi-muscle recording (12 muscles listed in C). Dots indicate the stimulated scalp sites. B: enlarged grid of the stimulated scalp sites. Numbers in the individual squares correspond to muscular clusters as detailed in C. Notice that there are areas with unspecific, generalised and low level of output (i.e. 5 and 6), while there are areas with selective outputs to groups of ‘proximal’ or ‘distal’ upper limb muscles (C). Percentages in C are referred to 100% as the maximal amplitude of each individual muscle. Hot spot in B is referred to the hand muscles.

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

evolution of a dipolar generator source, which is modelled as an Equivalent Current Dipole (ECD) able to explain 90% or more of the magnetic field scalp distribution and with a time resolution of one millisecond or less. Due to its physical properties, MEG allows a precise 3D-localisation of the firing neuronal pool [143] (Fig. 2). Besides the spatial properties of ECD, their strength (roughly reflecting the number of neurons synchronounsly firing) and orientation can also be measured. Moreover, response morphology provides indirect information on the underlying neural circuitries (Fig. 7). The ECD decrease or increase of dipole strength — on its own — can easily be due to restriction or enlargement of the responsive area (i.e. by the recruitment of a fringe of neurons surrounding those usually fired by the incoming stimuli). This can be due to dynamic phenomena, including modulation of use-dependent synaptic efficacy, or changes of excitatory / inhibitory modulation by adjacent or remote (diaschisis) lesioned brain areas, or by changes of the amount of sensory information. In this model, the centre of gravity of the responsive area is not modified by the ‘plastic’ reorganisation and the ECD baricentre remains stable. On the other hand, when a brain lesion affects the main bundle of afferents and / or their target relays in primary somatosensory cortex, the recovery of lost function is only achieved if a neural circuitry alternative to the damaged one is progressively activated. In this case, the centre of gravity (and the ECD baricentre) of the responsive area is shifted in space and the response morphology is changed. When combining MEG and TMS it is possible to replicate in humans some protocols from experimental neurophysiology, following unilateral changes of peripheral sensory input as well as in patients with monohemispheric lesions, with the aim of evaluating the long and short-term effects on cortical sensorimotor organisation and their interhemispheric differences. Such an approach started in recent years has to provide important tools to elucidate the problem, whether clinical recovery of sensory and motor functions is based upon the re-establishment of previously damaged — but not destroyed — cortico-spinal connections or upon ‘plastic’ rearrangements of cortical somatotopy, in which previously functionally silent or differently operating cortico-spinal fibres (activated in newly-established cortico-cortical connections) are vicariating the lost functions.

4. Experience-dependent and sensory deprivation brain reorganisations tracked via neuromagnetic methods

4.1. Deafness and musicians Previous studies with Event Related Potentials (ERP) have demonstrated that parietal regions are more strongly

137

activated by moving visual stimuli in deaf rather than in normal subjects [79]. Parameters of ECDs during MEG recordings in musicians with an absolute pitch as compared to non-musicians have been evaluated during different types of auditory stimulation represented by noise-burst and tones. Generator sources for noise-burst were significantly separated and posterior to ECDs for tones in both the hemipsheres of the musicians but not for the non-musicians. Such results have been ascribed to the presence of distinct neural activities in the auditory cortex of musicians, which may result from plastic reorganisation due to the training of inherent cortical structural specificity [45]. Enlargement of cortical representation in skilled musicians was correlated with the age at which the musicians began to exercise and does not differ between musicians with absolute or relative pitch [83]. The auditory system poorly matures in absence of appropriate acoustic stimulation [95] and unilateral sensorineural hearing loss may modify information processing in the central auditory pathways [138]. Moreover, the auditory system retains its plasticity during the period of deafness, since the re-introduction of stimulation by the cochlear implant both in childhood and in adult life. For instance, otosclerotic patients have been evaluated before and after corrective surgery, with significant recovery of air conducted auditory function [131]. The usual tonotopic organization of the auditory cortex during pure tone stimulation was missing in presurgical recordings (Fig. 3). Meanwhile, segregation of different frequencies in discrete cortical regions was reacquired post-surgery, together with significant improvement of acoustic function (Fig. 4)

4.2. Blindness Combined studies with Event Related Potentials and PET methods in blind humans indicated significant activation of visual areas by auditory stimuli, during haptic mental rotation and during reading the Braille alphabet. Brain TMS had showed an enlargement in the motor hand area representation in Braille readers: this was particularly evident in people who were already blind at birth [139,63,102,137,117,84]. Functional imaging studies of people who were blind from an early age have revealed that their primary visual cortex can be activated by Braille reading and other tactile discrimination tasks. Rapid and reversible modulation in motor cortical outputs can occur in relation to preceding activity. Cortical motor output maps, studied by means of transcranial magnetic stimulation, showed a larger motor output for the first dorsal interosseous (FDI) of the reading hand, after the working shift rather than in the morning after having been off work for 2 days. These changes were not evident in any other muscle (ADM) not implied in the reading Braille process [86]. Visual cortical areas can be activated by somatosensory input in blind subjects but not those with sight. The

Fig. 2. MEG technique. Top: the main steps of the MEG analysis to spatially identify the activated neural pools in response to an external delivered stimulus (in this example: contralateral median nerve electrical stimulation). Left: superimposition of the 25 recording channels in the 100 ms time interval starting from the stimulus onset. Centre: the magnetic field distribution at 21 ms after the stimulus (100 fentotesla — 10 215 — is the step between isofield lines) is characterised by the ‘dipolar’ shape. When this fields distribution appears, the source generating them is well modelled by an Equivalent Current Dipole (ECD). Right: spatial position identification of the activated source. It is expressed in a co-ordinate system defined on the basis of the anatomical landmarks (indicated by the black dots). Bottom: defining a reference system common to MEG spatial identification and MR images, it is possible to identify the subjective anatomical feature of the functionally activated neuronal area. (From P.M. Rossini, F. Pauri, Contribution of neuromagnetic integrated methods in evaluating cerebral mechanisms of plastic reorganization in monoemispheric stroke, Neuroscience News 2 (1999): 1–15 with permission).

138 P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

139

Fig. 3. (a) N100 m ECD positions in one control subject, in response to 250 (a), 500 (b), 1000 (c), 2000 (d) Hz tone bursts, showing the relation between ECD depth and the x-coordinate. Superimposition with MRI confirms dipoles positioning within the depth of the supra-temporal Silvian fissure. (b) Mean values of the N100 m ECD x-coordinate in the two groups of normal hearing subjects stimulated at 50 [closed circle] and 20 dB HL [open circle]. (From Tecchio et al. [131], with permission).

significance of this cross-modal plasticity is unclear, as it is not known whether the visual cortex can process somatosensory information in a functionally relevant way.

Cross-modality plasticity in blind subjects contributes to sensory compensation when vision is lost early in life. TMS has been used to disrupt the function of different

140

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

Fig. 4. (a) As in Fig. 3b comparing N100 m ECD x-coordinates in normal hearing subjects [closed circle] and patients before [open square] and after surgery [closed square]. (b) Tonotopic extension difference between POST- and PRE-surgery times in relation to the period duration following the operation. (c) An explanatory scheme describing an hypothesis about the cortical areas reorganization in patients before surgery respect to control subjects: the ECD activated by different tones appeared spatially overlapping (black dots, representing the ECD positions, i.e. the neuronal activated areas baricentres, show average distance from 9 mm in controls to 2 mm in patients). Rectangles represent neuronal regions activated by different tones and their areas the number of synchronously firing neurons (measured by the ECD strength): areas remain the same for all frequencies in control and patients, provided the same intensity of stimulation above subjective threshold is used. (From Tecchio et al. [131], with permission).

cortical areas in people who were blind from an early age as they identified Braille or embossed Roman letters. Stimulation of the occipital (visual) cortex induced errors in both tasks and distorted the tactile perceptions of blind subjects; this had no effect on tactile performance in normal-sighted individuals, whereas it is known to disrupt their visual performance. Blindness from an early age can cause the visual cortex to be recruited to for the purpose of somatosensory processing. This cross-modal plasticity may account in part for the superior tactile perceptual abilities of blind subjects [23]. Less is known on about the amount of reorganisation when visual loss occurs at an older age. Repetitive TMS inducing transient dysfunction during Braille reading of the occipital cortex induced severe inability only in congenitally and early-onset blind persons, but not in late onset blinds individuals. Similarly, the PET scan showed a consistent activation of the occipital cortex during Braille reading only in the early onset or congenitally blind [24]. PET study demonstrated that congenitally blind subjects show task-specific activation of extrastriate visual areas and parietal association areas during Braille reading, whereas those who lost their sight after puberty show

additional activation in the primary visual cortex with the same tasks. Studies in blind-raised monkeys show that crossmodal responses in extrastriate areas can be elicited by somatosensory stimulation. Since primary visual cortex does not show crossmodal responses in primate studies, the differential activation in late and congenitally blind subjects highlights the possibility of reciprocal activation by visual imagery in subjects those with early visual experience [11].

4.3. Motor learning In a recent polished study, Liepert et al. [70] showed that a short-lasting training of synchronous movements of the thumb and the foot induced a transient and mean shift of 7 mm of the center of gravity of the hand muscle (APB) medially toward the foot area which vanished after about 1 h. This modulation of the motor output has been ascribed to interactions between hand and foot representation areas in the motor cortex. Performance of complex motor tasks, such as rapid sequences of finger movements, can be improved in terms of speed and accuracy over several weeks by daily practice

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

sessions. TMS was used to study the role of plastic changes of the human motor system in the acquisition of new fine motor skills. The cortical motor areas targeting the contralateral long finger flexor and extensor muscles in subjects learning a one-handed, five-finger exercise on the piano, enlarged and the activation threshold decreased after a 5-day course [87]. The process of acquiring motor skills through the sustained performance of complex movements is associated with neural plasticity. Focal TMS of the motor cortex was used to evoke isolated, directionally consistent thumb movements in or near a recently practised direction of thumb movements for several min before returning to the original direction. Substantially smaller effects followed more direct stimulation of corticofugal axons with transcranial electrical stimulation, pointing to cortex as the site of plasticity. The training rapidly, and transiently, established a change in the cortical network which encoded kinematic details of the practiced movement [21]. Long-term, experience-dependent reorganisation of the adult MI, which may underlie the acquisition and retention of the motor skill were demonstrated. Functional magnetic resonance imaging showed the extent of cortex activated by the practised sequence was enlarged, compared with the unpractised sequence, after 4 weeks of training. These changes persisted for several months [57]. MEG revealed enlarged cortical representation of the digits of the left hand of the string player. The amount of cortical reorganisation was correlated with the age of playing onset. Representations of body parts depends on the use and changes related to the personal experience; this, sometimes, induces use-dependent, aberrant plastic brain reorganisation which are the substrates of neurological deficits. For example, focal dystonia is associated with the repetitive synchronous movements of the digits, which is part of some human activities (i.e. musicians). MEG recordings have shown that the mean distances of ECDs corresponding to digits in SI is smaller (fusion?) for the affected hand of dystonic musicians, compared to the non-affected hands or to the hands of control subjects who were non-musicians [32]. Mental imagery of movements, not followed by overt contraction, may increase the capability of acquiring new motor skills. Such a technique has been successfully applied as a training procedure, in order to improve the actual performance without receiving any feedback about the results. TMS represents an excellent tool to objectivate motor output changes taking place during the ideation of movements. Izumi et al., described facilitatory effects (5decrease of threshold for excitability) induced by thinking about movement. Non-motor mental activity and alerting stimuli ‘per se’ could potentiate MEPs amplitude in strict relationship with desynchronization of the background EEG activity of the stimulated brain areas. Movement imagery can focus specific facilitation on the prime-mover muscle for the mentally simulated movement [103,110].

141

5. ‘Peripheral’ and ‘Central’ lesions affecting sensorimotor brain areas functionality. Follow-up of recovery.

5.1. Peripheral nerves lesions and limb amputation Merzenich et al. [75,76] demonstrated for the first time that mechanisms perhaps identical to a part of the original developmental organising processes are operational throughout life in projection systems in primates. They transected and ligated the median nerve in adult owl and squirrel monkeys. After several months, the cortical areas representing the nerve within skin surface representations in areas 3b and 1 were completely occupied by ‘new’ and expanded representations of skin fields surrounding the denervated skin districts. There was no evidence that these skin surfaces were represented in this cortical region prior to median nerve transection; moreover, these skin surfaces retained their normal representation elsewhere within these two cortical representations of hand surfaces. Furthermore, large ‘new’ representations of the dorsal surfaces of digits 1 and 2 (innervated by the radial nerve) and large ‘new’ representations of the hypothenar eminence (innervated by the ulnar nerve) were found. These expanded representations of alwaysinnervated skin sometimes appeared to move entirely into the former median nerve representational zone [76]. The cortical representations of the hand in area 3b in adult owl monkeys 2–8 months after surgical amputation of digit 3, or of both digits 2 and 3, showed that the representations of adjacent digits and palmar surfaces expanded topographically to occupy most or all of the cortical territories formerly representing the amputated digit(s). This was accompanied by increases in the cortical magnification factor, surrounding skin surfaces being represented in correspondingly finer grain, which implies that the rule relating receptive field overlap to separation in distance across the cortex was dynamically maintained as receptive fields progressively decreased in size. The discontinuities between the representations of the digits underwent significant translocations (usually by hundreds of microns) after amputation. Sharp, new and discontinuous boundaries, where the usually separated, and expanded digital representations (e.g., of digits 1 and 4) approached each other in the reorganising map were observed, implying that these map discontinuities are normally maintained in dynamic ways. Changes in receptive field sizes with an expansion of representations of surrounding skin surfaces into the deprived cortical zone had a spatial distribution and a time course similar to changes in sensory acuity on the stumps of human amputees [77]. Following upper extremity amputation in humans, ECD locations revealed that the tactile stimulation of the lip evoked responses, not only in the area of the somatosensory cortex corresponding to the face, but also within the cortical region that would normally correspond to the amputated hand. This ‘invasion’ of the cortical amputation

142

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

zone was accompanied by a significant increase in the size of the representation of the digits of the intact hand, presumably as a result of an increased importance of sensory stimulation consequent to increased dependence on that hand imposed by the loss of the contralateral extremity [33]. Reorganization of the motor system can be present up to 2 years following amputation. For example, Roricht et al. [101] have found seven out of eight subjects with forearm amputation with an increasingly larger representation of the biceps muscle; this pattern was less evident at more proximal sites of amputation, measuring MEPs on the deltoid muscle. In amputees at the elbow, MEG revealed a strong correlation between the amount of cortical invasion of the deafferented arm cortex by the one devoted to lips and the amount of pain-evoked sensation mislocalized to the phantom limb [35]. Re-examination of phantom limb patients was performed, in order to corroborate the phenomenon of mislocalization. The topography of referred sensation had completely changed in every patient. These results suggest that, while the overall extent of reorganization is a rather stable phenomenon, the concomitant changes in the pattern of sensory processing are not stable. This may be due to the fact that alterations of sensory processing are not hardwired, but are rather mediated by an extensive and interconnected neural network with fluctuating synaptic strengths [61]. Positron emission tomographic measurements of regional cerebral blood flow in traumatic amputees, in whom phantom limb symptoms were prominent, showed significant blood flow increases in the contralateral MI / SI cortex over a wider area and of significantly greater magnitude in the partially deafferented cortex contralateral to the amputation. In congenital amputees, without phantom limb symptoms, blood flow increases were also present over a wider area in the partially deafferented MI / SI cortex, but their magnitude was not significantly different from that in the normally innervated MI / SI cortex. TMS studies showed that the abnormal blood flow increases in the partially deafferented MI cortex of traumatic amputees were associated with increased corticospinal excitability [60].

5.2. Spinal cord lesions and motoneuron diseases In patients with traumatic section of the spinal cord at the lower cervical cord level, the focal magnetic-coil elicited compound motor action potentials (CMAPs) from most caudal muscles spared by the lesion (biceps and deltoid) from a much wider area of scalp than in the normal subjects. Latency of biceps and deltoid CMAPs were inversely related to CMAP amplitude. In patients with traumatic quadriplegia, a reorganization of the motor cortical projection system is inferred, in which areas normally eliciting digit movements instead activate muscles in quadriplegics just above the level of spinal cord lesion. The reorganization applies also to the central sense

of movement normally elicited by focal frontal cortex stimulation [69]. MEPs in patients with a previous history of paralytic poliomyelitis showed that changes of increased excitability and volume of motor output were evident only for deltoid muscle on the ‘affected’ arm with respect to the contralateral one, while no differences were noticed for the APB muscle [81].

5.3. Monohemispheric brain lesions When damage to a functional system is partial, a withinsystem recovery is possible, whereas after complete destruction, substitution by functionally related systems remains the only alternative [122]. The importance of the pyramidal system for motor function — mainly upper limb and hand — is well known; experimental and clinical studies have shown that approximately 1 / 5 of the pyramidal fibers are sufficient to ensure restitution of fractionated hand finger movement. Hence, a within-pyramidal system reorganization — when possible — is a major candidate for functional recovery of motor control of upper limb and hand [14,50,65,66,140,40,19,111,134,135,133]. Functional reorganization of the motor output following an hemispheric stroke has been repeatedly reported [111,134,135,112,16]. In several of such reports an excessive asymmetry of the hand muscle motor maps between the Affected and the Unaffected Hemispheres (AH vs. UH) have has been demonstrated; such ‘map migration’ was usually on the medio-lateral axis, but an anteroposterior shift of up to several millimeters of the map’s center of gravity have been also observed. This has been particularly true in patients in the chronic stages of brain lesions and represented a dynamic phoenomenon when a follow-up was carried out alongwith over the immediate months following stroke [19,134,135,16]. Meanwhile, clinically relevant literature has been devoted to investigating the role played by the cerebral hemisphere ipsi- and contralateral to an ischaemic insult in the acute and subacute stages of functional recovery from stroke deficits [68,18,48]. The most popular term for these remote effects of stroke remains ‘diaschisis’, which implies the idea that acute neuronal failure in the ischaemic area would induce remote modulatory effects on cortical excitability of unaffected districts of the same hemisphere, via cortico-cortical connections, and of the contralateral Unaffected Hemisphere via transcallosal fibres [3,25]. Examples of such a mechanism are offered by the metabolic enhancement followed by progressive depression of the UH, as documented by PET and SPECT in ‘acute’ and ‘subacute’ post-stroke epochs [6]. Moreover, transient hyperexcitability of the unaffected hemisphere contralateral to the neocortical infarction has been documented in animal models [12,59] and is considered as one of the major causes of post-stroke recovery linked with plastic reorgani-

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

sation phenomena [41]. The relationship between the amount of clinical recovery after stroke and the information gathered via transcranial magnetic stimulation in the early (h or days) stages aimed to find a prognostic tool of clinical evolution in the first days of the cerebrovascular lesion, has been extensively studied [43,17,90,7]. In recent years, it has been shown that MEPs from proximal and distal upper limb muscles are always elicitable in stroke patients who recover full control of finger movements [43,136]. Less attention was devoted in following up brain excitability changes in the so-called subacute and chronic stages (weeks, months) and in correlating them with the clinical outcome. The astonishing discrepancy distinguishing functional recovery between the acute vs. chronic stages of brain lesions raises the possibility that reorganisation is not restricted to within-system recovery taking place in corticospinal tract contingent from the motor cortex. Meanwhile, sensory feed-back is also very important for motor recovery. Patients with poor or no recovery of motor function following a monohemispheric stroke frequently show a severe thalamic metabolic depression or a profoundly abnormal electromagnetic responsiveness of SI cortex [111,123,82]. The role of substitution by other non-pyramidal efferents — (i.e. the bilaterally organised premotor / reticulo / spinal projection) is still unclear. One clinical example of the reorganization of brain motor output is based upon the frequent observation of normal or nearly normal motor dexterity in patients with large, but slow growing tumors in the motor cortex area. It has been postulated that such a function is maintained by the engagement of populations of neurons adjacent to those of the normal hand representation (i.e. extending muscles representation into parietal or premotor cortex [122]). In fact, large-scale reorganisation in MI beyond the boundaries of physiologic cortico-cortical connections probably requires long-term periods of repetitive engagement [126]. Evidence for the reorganisation of the human motor cortex allowing preservation of hand function in brain tumors has been shown [144]. The mapping of the regional cerebral blood flow changes related to voluntary finger movements in patients with tumours occupying the hand motor area has shown activation solely outside the tumour volume. Compared with the unaffected side, the activation was shifted either along the mediolateral body representation of the motor cortex or into the premotor or parietal somatosensory cortex. Slowly developing lesions can induce large-scale reorganization that is not confined to changes within the somatotopic body representation in motor cortex [124]. Maturational plasticity on motor activations for the affected hand in patients with unilateral lesion involving the rolandic cortex was shown by PET studies. Rolandic activations in the contralesional hemisphere were enhanced in two groups of patients with early and late onset lesion when compared to normal adults.

143

Secondary motor and frontoparietal nonmotor cortices were more activated in the early than in the late lesion group, suggesting a greater potential for reorganization during early development than later in life [78]. Cortical plasticity of motor output has been investigated in cerebral palsy patients with bihemispheric lesions. In those with cerebral palsy from birth, a significant lateral shift of motor maps has been reported for lower limb muscles; moreover, the ipsilateral pathways both to upper and lower limbs are more excitable during TMS [71]. Our experience extends to patients at different stages following a monohemispheric stroke defined, according to the WHO criteria, as a syndrome of rapidly developing clinical signs of focal or global disturbance of cerebral functions with no apparent causes other than vascular. On the basis of a TC scan or / and a MRI, lesions were classified as ‘cortical’ (C), when mainly the cortical areas were involved or the lesion extended to subcortical white matter excluding basal ganglia and internal capsule, and ‘subcortical’ when the thalamus, caudate nucleus, lenticularis nucleus or internal capsule were affected. For the ‘acute’ stage, standard procedures [108,109] of brain TMS were carried out 24–72 h after admittance to the hospital (Ta), a week after the first recording session (Tb) and six months later (Tc) (Fig. 5). Data obtained from the UH in each recording session did not differ from those obtained in normal subjects, whereas the responses from the AH changed significantly during follow-up. In (Ta) the excitability threshold was significantly higher in the AH, compared with the UH and with normal subjects (P,0.001). MEPs from ADM and Deltoid, were absent in 33% and 30% of patients respectively. Latencies of MEPs were significantly prolonged and showed a lower than normal amplitude, especially during the contraction. Central conduction time was selectively and asymmetrically prolonged (P,0.002) from the AH. Interhemispheric differences between affected and unaffected hemispheres were significant for all the parameters studied. A large number of the patients (60%) showed a clinical improvement or no changes (40%) in the first week after the stroke (Tb); none of the patients showed a worsening of their clinical conditions. Neurophysiological data showed a partial recovery during follow-up: latencies of MEPs decreased and amplitudes increased, but they were still altered at the end of the period of observation. The excitability threshold was still significantly higher in the AH and CCT prolonged (P,0.001). Clinical improvement was evident six months after the cerebrovascular accident in all patients who underwent the third recording session (Tc). The absolute values of neurophysiological parameters had similar improvement and — at the end — showed no significant differences compared with those obtained from the normal subjects, excluding the CCT that was still prolonged (P5 0.03). Meanwhile, at (Tc), there were no significant interhemispheric differences between affected and unaf-

144

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

Fig. 5. M.D. male 67 years, presenting left hemiplegia due to a right hemispheric lesion. In the first recording, 48 h after the stroke, there were no recordable MEPs when the affected hemisphere was stimulated (A), but when the patient was invited ‘to think to move’ his hemiplegic arm, it was possible to record motor potentials, even if the amplitudes were lower and the latencies prolonged compared with those of the unaffected side (At). There were no recovery in the second recording session (B) a week after the stroke, whereas MEPs reappeared six months later (C). On the clinical ground, patient showed a partial recovery of the motor control of both arm and leg six months after the stroke. (From P.M. Rossini, F. Pauri, Contribution of neuromagnetic integrated methods in evaluating cerebral mechanisms of plastic reorganization in monoemispheric stroke, Neuroscience News 2 (1999): 1–15 with permission).

fected hemispheres, excluding the excitability threshold. The amplitudes of MEPs obtained from the affected ADM were positively correlated with the Canadian Score values: not only the higher the MEP amplitude, the higher the Canadian Score in (Ta) (r50.633, P,0.001) in (Tb) (r5 0.576, P50.005), but also the higher the MEPs amplitude in (Ta) the higher the Canadian Score in (Tc) (r50.613, P50.001). It can be deduced that the larger the MEP is in the ‘acute stage’, the better the prognosis is for clinical recovery and final outcome. No correlation was found between the side (right and left) and the type of the lesion (cortical or subcortical) and the neurophysiological parameters. In another group of stroke patients, changes of hemispheric motor output were analysed in a ‘clinical stabilised’ condition ($60 days) following stroke. In order to con-

struct a map of the cortical motor output of the hand, eleven positions on each hemiscalp were scanned, covering the pre-central area, delivering the TMS via a focal 8shaped coil. Recordings were performed in the first session (T1), when the lesion was stabilised, about 8 weeks from the stroke event and repeated about 8–10 weeks from T1 (T2). The Barthel index for disability and the Canadian Neurological Scale with subscoring for hand functionality (Hand Motor Score) were acquired. Excitability thresholds in the Affected Hemisphere (AH) were significantly higher and the MEP amplitude smaller despite stronger TMS were being employed. In the AH, the area of cortical output to the target muscle was also significantly and asymmetrically restricted, compared with normals [20] and with the patients’ Unaffected Hemisphere

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

(UH). The percentage of altered parameters was significantly higher in T1 and in those suffering from subcortical lesions. This could probably be ascribed to a large number of densely packed fibres affected by a subcortical lesion and to a less efficient short-term ‘plastic’ reorganisation, possibly due to a longer time in achieving complete retrograde degeneration and in activating new synaptic connections (Fig. 6). In T2, the ‘subcortical’ patients presented an amelioration of the neurophysiological parameters reaching the same level of the ‘cortical’ group. Anomalous ‘hot spot’ sites were observed more frequently in the cortical group. In fact, recovery in cortical patients with anomalous ‘hot spot’ sites might rely on the activation of brain areas outside the usual boundaries of the primary motor cortex. Therefore, this finding might represent a neurophysiological marker of plastic rearrangements of cortical motor output. A significant enlargement of the hand motor cortical area from AH was found in T2 compared with T1 in 67% of cases: this was usually coupled with clinical improvement, as shown by the Hand Motor Score, and the Barthel Index and the Canadian Neurological Scale. It is worth mentioning that those

145

patients demonstrating an enlargement of the hand area also showed a correlated improvement of the hand score. The level of lesion (cortical or subcortical) did not influence the final clinical outcome. These findings suggest that a remarkable reorganisation of the motor output from the lesioned hemisphere is still taking place 3–4 months after the stroke. The time course and degree of motor recovery in humans could largely depend on the amount of the previously described distributed motor network lesioning, since different motor areas operate in a parallel rather than in a hierarchical fashion. Moreover, such parallel descending pathways might be able to substitute functionally for each other [37]. MEPs recording in the early stroke stages cannot always assess the amount of corticospinal tract fibre integrity because the enhanced Excitability Threshold, as well as the partial or total nerve impulse conduction block — (partial or total) — might be due to transient perilesional oedema and or diaschisis. However, the post-lesional timing of the study was long enough to suggest that the observed modifications are due to corticospinal tract reorganisation, rather than to recovery from perilesional oedema and

Fig. 6. In A (left): sites of scalp stimulation, (right): one healthy control subject. The size of black dots indicate the amount of motor output as represented by MEPs amplitude. B: CF, male 62 years, mainly cortical lesion. Tracings and CT scan showed in T1 the inexcitability of the AH, even with maximal intensity of the stimulator output. In T2 several responsive sites were identified on the AH, even if it was not possible to recognise a clear-cut ‘hot spot’. Clinical recovery of hand functionality was relatively good. (Partially modified from Cicinelli et al. [19] with permission).

146

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

cortical hypoexcitability. Recovery of sensory deficits can also play a significant role, since the modulation of the tonic sensory flow from the skin enveloping the target muscle significantly affects the amount of its cortical representation [113,114]. Short- and long-term plastic ‘reorganisation of the somatosensory system’’ connected with hand and fingers were investigated via MEG methods. For the long-term plasticity protocol, Somatosensory Evoked Fields (SEFs) were recorded following separate electrical stimulation of the median nerve at the wrist, as well as the thumb and the

little fingers of both hands. The left and right little finger, the thumb and the median nerve at the wrist were separately and electrically stimulated. Intensities were set at about twice the subjective threshold of perception for fingers and just above motor threshold for the nerve at the wrist. Responses were recorded on the hemiscalp contralateral to the stimulated side over the parietal region. Only the initial part of SEFs, which contains the most stable, repeatable waves that are also independent from the subjects attention (N20 m, P30 m), were analysed. Equivalent Current Dipole (ECD) characteristics (spatial co-ordi-

Fig. 7. Top: motor maps of the right ADM muscle in the left hemisphere of one representative subject before and after anaesthetic block on the right median and radial nerves at wrist by injecting mepivacaine (10 ml at 0.5%) in the proximity of the nerve trunks. For each of the scalp positions stimulated, 6–8 MEPs were gathered and their mean value was assigned to each position for computing the map. Isofield maps (originally represented in 16 colour gradation) of each tested muscle were produced via a cubic interpolation algorithm. Note that post-anaesthesia amplitude values are higher and, in this subject, Abductor Digiti Minimi representation is enlarged. Bottom: same organisation as before, for MEPs from the right First Dorsal Interosseum muscle entirely covered by anaesthetised skin. Cortical representation of this muscle following anaesthesia is restricted, its maximal site being unchanged despite a significant lowering of MEPs amplitude (i.e. higher threshold). Each map represents a 3 by 3 cm square on the left hemisphere just in front of the intermeatal line, about 4 cm lateral to the nasion–inion line (from Rossini et al. [107], with permission).

Fig. 8. In the left: SEFs morphology after stimulation of the right median nerve, the thumb and the little finger, in a healthy subject. In the right: illustrative drawing of a brain slice parallel to the x2 y plane and cutting the central sulcus explaining the first three parameters: (A) loc parameter: the distance — expressed in millimetres — between the projection of the median nerve ECD location in the right hemisphere (Mn iR , black dot) and the average ave location across all the subjects (Mn R , empty dot). (B) hand parameters: the distance — expressed in millimetres — between the thumb (T R ) and little finger (L R ) ECD location in the right hemisphere. (C) loc asy parameter: the distance — expressed in millimetres — between the projection of the right median nerve ECD location (Mn R ) in the left hemisphere (Mn R9 ) and the left median nerve (Mn L ).

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154 147

148

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

nates and strength) were calculated at 1 ms intervals in the 15–50 ms post-stimulus epoch. The ‘hand extension’ was also calculated as the linear distance in millimetres between the centres of the ECD, activated by stimulation of the fifth and the first fingers of the contralateral hand. Brain MRIs were performed and the MEG–MRI common reference system was defined on the basis of three anatomical landmarks (vit. E capsules) fixed on nasion, left and right preauricolar points (Fig. 2). Recordings were performed at least 9 weeks after the onset of the monohemispheric, first-ever stroke. Neurological examination was carried out one or two days before the recording session: hand disability scores were assessed for each subject through the subscore for hand disability of the standardised Canadian Neurological Scale; sensory impairments were quantitatively evaluated by a 4-degree scoring system. All the SEFs parameters, including interhemispheric differences, had been previously tested in a group of healthy subjects [115,133,132] and the abnormality threshold was fixed at 2.5 SDs from the control means. Twelve out of 19 patients (63%) with reliable SEFs from the AH, showed an excessive interhemispheric asymmetry of signal strength at least for one stimulated district, and a total of 15 ECD pairs from homologous districts exceeded the normative range. Strength abnormalities affected more the P30 m component. When latency delays were accompanied by ECD spatial displacements, these always affected the N20 component generator sources. The MEG / MRI integration showed all ECDs localised outside the areas of anatomical lesion; interestingly, even displaced hand areas maintained the classical ‘homunculus’ somatotopy seen in the healthy hemispheres (the thumb being more lateral, the little finger more medial and the median nerve lying in between). Abnormalities include a significant enlargement of the hand extension in the AH, with a medial shift of the little finger, and the tendency of both fingers representations to shift anteriorly (Figs. 8, 9). It is worth underlining that abnormal parameters were also encountered in UH. Spatial displacements of ECDs did not mirror each other in the two hemispheres: in fact, 5 / 7 ECDs located outside of the normative limits in the UH were also excessively asymmetrical with respect to the homologous ECD in the AH. Larger cortical reorganisation leading to interhemispheric asymmetry — as reflected by major spatial interhemispheric ECDs asymmetries and / or enlargement of hand extension — correlated with poorer clinical recovery (both for sensory and motor performances) than when ECD localisation remained symmetrical. Analysis of wave shape interhemispheric correlation, when carried out in normals or in patients without ECD displacements, showed an extremely high value, due to a nearly identical correspondence of peaks morphology and latency between the two hemispheres. On the contrary, the correlation coefficient dropped to very low levels whenever ECD displacements were present.

Fig. 9. F.R., male 62 years old, ischaemic small lesion in the region of the right basal ganglia (arrow (a); no sensory deficits and partial recovery of motor weakness. MEG / MRI integration shows the asymmetrical location of ECDs activated by fifth finger’s stimulation at the two successive MEG-examinations: respectively UH (b) and AH (c) at 1 month — black circle — and 24 months — black square. Such an interhemipsheric asymmetry increased at 24 months. In (d), the projection of thumb and little finger ECDs (at 24 months) on the same illustrative axial section for UH and AH, note the frontal shift of both ECDs and the medial dipslacement of the little finger ECD, determining the ‘hand extension’ enlargement. (From Rossini et al. [112], with permission).

This suggests the possibility of newly-established neural networks which justify a change of response morphology on the AH. Within this frame, it is suggested that new brain areas which are not usually reached by a dense connection with hand and finger sensory receptors may act as primary somatosensory hand centres and allow progressive clinical recovery from a vascular insult. Moreover, it is evident that it is useful to investigate interhemispheric asymmetry of primary sensory and motor hand areas as a tool for identification and follow-up of neuronal reorganisation after a focal, monohemispheric, brain lesion (Fig. 10, from [130]).

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

149

Fig. 10. Description of parameters chosen to evaluate the SEF shape correlation. The shape analysis comparing SEF morphologies in different subjects or the two hemispheres in the same subject was conducted by selecting the two channels with opposite polarity and maximal amplitude in each hemisphere, calculating the correlation between each of the two channels and the one in the corresponding cerebral region of the other hemisphere, and averaging these two correlation indexes. The parameters were calculated for the 30 ms interval following the M20 onset (5IHC sm1) and for the succeeding 50 ms interval ] (5IHC par). The parameter distribution did not result gaussian-shaped and the following transformation allowed to achieve the best fit: y 5 ln(1 2 x), ] where x5IHC sm1 (or IHC par). (From Tecchio et al. [130]). ] ]

6. Conclusion Animal experiments have clearly shown that some plastic rearrangements of the CNS functions secondary to peripheral — nerve / roots — or cerebral lesions not only occur in childhood, but are also present in adulthood [75]. A robust body of experimental evidence now supports the hypothesis that neuronal aggregates adjacent to a lesion in the sensorimotor brain areas can progressively vicariate the function previously played by the damaged neurones. Such a reorganisation should significantly modify the interhemispheric asymmetries of somatotopic organisation of the sensorimotor cortices and largely subtend clinical recovery of motor performances and sensorimotor integration. Brain-functional imaging studies describe the recovery from hemiplegic stroke to be associated with a marked reorganisation of activation patterns of specific brain structures [18]. Moreover, TMS and MEG techniques nicely demonstrate the short-term reorganisation of sensorimotor cortical areas topography in the healthy following sensory deprivation from the periphery (Fig. 7; [107,113,114]). Finally, long-term reorganisation of these areas are demonstrated in blind adults learning the Braille method [86] and in amputees suffering from ‘phantom limb syndrome’ [35]. Other models of topographic modifications in hemispheric somatotopy are related to motor learning: in adults, they include musicians and the effects

of repeated motor imagery [31,103]. It is, therefore, relatively well established that short- and long-term reorganisation of cortical input–output flow during learning and following a lesion and rehabilitation procedures is active in adults, and that TMS–MEG techniques are able to provide important tools for the amount and mechanisms of such reorganisations. Findings in stroke patients suggest that the AH often undergoes a significant ‘remodelling’ of sensory and motor hand somatotopy outside the ‘normal’ areas, and / or an enlargement of the hand representation. The UH also undergoes a reorganisation process, even if to a lesser degree. Since the absolute values of the investigated parameters relatively fluctuate across subjects due to individual anatomical variability, it is worth knowing that they vary very little in their interhemispheric differences due to the fact that individual morphometric characters are mirrored on both hemispheres. Thus, an excessive interhemispheric asymmetry of the sensorimotor hand areas seems to be the parameter with the highest sensitivity in describing the brain reorganisation following a monohemispheric lesion. Mapping motor and somatosensory cortical areas through focal TMS and MEG is useful to investigate hand representation and to detect interhemipsheric asymmetries in normal subjects and in patients [36]. Such techniques allow the detection of sensorimotor areas reshaping, either due to neuronal reorganisation or to

150

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

Fig. 11. Overview of patient data including MRI coronal view of the site and the extent of post-stroke lesion in the left hemisphere (top left), the MEG–ECDs location (left: light blue corresponds to the little finger; green to median nerve and orange to the thumb), the representation of fMRI activated areas (right: red voxels correspond to the right hand movements, yellow voxels to the left hand movements) the TMS map (top centre red: hot spot). Numbers on the left of axial slices correspond to the slice planes in the sagittal views (centre). Note that the hand area in the AH is asymmetrically more lateral and posterior than in the UH. A similar type of displacement with respect to the UH, mainly due to the displacement of the thumb ECD, which was closer to the lesion. Maps of the motor output as obtained via focal TCS are asymmetrical, due to the posterior enlargement of the output from AH (from Rossini et al. [111], with permission).

recovery of the previously damaged neural network. They have a high temporal resolution but suffer from limitations: TMS only provides bidimensional scalp maps, and MEG give three-dimensional identification of sources obtained by means of inverse procedures that rely on the choice of a mathematical model of the head and sources. Moreover, these techniques do not test movement execution and sensorimotor integration as they are utilised in everyday life. Functional MRI may provide the ideal means to integrate the findings obtained with the other two techniques. In one paradigmatic case (Fig. 11; [111,112]), structural MRI data have been integrated with the brain imaging techniques: of fMRI, TMS, MEG in studying recovery from stroke. This combined approach has demonstrated changes in the topography of sensorimotor brain area devoted to hand control, showing a common trend regarding the source reorganisation in the AH. In our opinion, this multitechnological combined approach is, at the present moment, the best way to test the presence and amount of plasticity phenomena underlying partial or total recovery of hand function. In conclusion, neuromagnetic recordings are of relevant value in providing information on the excitability, extension, localisation and functional hierarchy of sensorimotor

brain areas during motor learning, as well as sensorimotor integration in both the healthy and in neurological patients.

Acknowledgements The author acknowledges the pivotal role played by Drs P. Cicinelli, R. Traversa, P. Pasqualetti, A. Orlacchio, D. Lupoi, M. Oliveri, M. Filippi, F. Tecchio, V. Pizzella, GL Romani, S. Rossi in providing for clinical records and data analysis and thanks of the technicians E. Fusco and M. Ercolani for the TMS recordings. Research was partially funded by Italian ‘Ministero del Lavoro’ grant research project n8 1091, and Italian Council for Research, grant n8 93.01767.04

References [1] E. Ahissar, E. Vaadia, M. Ahissar, H. Bergman, A. Arieli, M. Abeles, Dependence of cortical plasticity on correlated activity of single neurons and on behavioral context, Science 257 (1992) 1412–1415.

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154 [2] P. Andersen, P.J. Hagan, C.G. Phillips, T. Powell, Mapping by microstimulation of overlapping projections from area 4 to motor units of the baboon’s hand, Proc. R. Soc. Lond. B. Biol. Sci. 188 (1975) 31–36. [3] R.J. Andrewes, Transhemispheric diaschisis, Stroke 22 (1991) 943– 949. [4] H. Asanuma, C. Pavlides, Neurobiological basis of motor learning in mammals, Neuroreport 8 (1997) 1–6. [5] A.T. Barker, R. Jalinous, I.L. Freeston, Non invasive stimulation of human motor cortex, Lancet 1 (1985) 1106–1107. [6] J.C. Baron, D. Comar, M.G. Bousser, P. Castaigne, Crossed cerebellar diaschisis in human sopratentorial infarction, Trans. Am. Neurol. Assoc. 105 (1980) 459–461. [7] R. Benecke, B.U. Meyer, H.J. Freund, Reorganization of descending motor pathways in patients after hemispherectomy and severe hemispheric lesions demonstrated by magnetic brain stimulation, Exp. Brain Res. 83 (1991) 419–426. [8] L.J. Bindman, K.P. Murphy, S. Pockett, Postsynaptic control of the induction of long-term changes in efficacy of transmission at neocortical synapses in slices of rat brain, J. Neurophysiol. 60 (1988) 1053–1065. [9] T.V. Bliss, T. Lomo, Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path, J. Physiol. (Lond). 232 (1973) 331–356. ` A. Pascual-Leone, V.E. Amassian, R. [10] J.P. Brasil-Neto, J. Valls-sole, Cracco, P.J. Maccabee, J. Cracco, M. Hallet, L.G. Cohen, Rapid modulation of human cortical motor outputs following ischaemic nerve block, Brain 116 (1993) 511–525. [11] C. Buchel, C. Price, R.S. Frackowiak, A. Friston, Different activation patterns in the visual cortex of late and congenitally blind subjects, Brain 121 (1998) 409–419. [12] I. Buchkremer-Ratzmann, M. August, G. Hagemann, O.W. Witte, Electrophysiological transcortical diaschisis after cortical photothrombosis in rat brain, Stroke 27 (1996) 1105–1111. [13] H. Buchner, U. Reinartz, T.D. Waberski, R. Gobbele, U. Noppeney, M. Scherg, Sustained attention modulates the immediate effect of de-afferentation on the cortical representation of the digits: source localization of somatosensory evoked potentials in humans, Neurosci. Lett. 260 (1999) 57–60. [14] P.C. Bucy, Stereotactic surgery: philosophical considerations, Clin. Neurosurg. 11 (1964) 138–149. [15] D.V. Buonomano, M.M. Merzenich, Net interaction between different forms of short-term synaptic plasticity and slow-IPSPs in the hippocampus and auditory cortex, J. Neurophysiol. 80 (1998) 1765– 1774. [16] M.L. Byrnes, G.W. Thickbroom, B.A. Phillips, S.A. Wilson, F.L. Mastaglia, Physiological studies of the corticomotor projection to the hand after subcortical stroke, Clin. Neurophysiol. 110 (1999) 487–498. [17] A. Catano, M. Houa, J.M. Caroyer, H. Ducarne, P. Noel, Magnetic transcranial stimulation in non-hemorrhagic sylvian strokes: interest of facilitation for early functional prognosis, Electroenceph. Clin. Neurophysiol. 97 (1995) 349–354. [18] F. Chollet, V. Di Piero, R.J.S. Wise, D.J. Brooks, R.J. Dolan, R.S.J. Frackowiak, The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography, Ann. Neurol. 29 (1991) 63–71. [19] P. Cicinelli, R. Traversa, P.M. Rossini, Post-stroke reorganization of brain motor output to the hand: a 2–4 month follow-up with focal magnetic transcranial stimulation, Electroencephalogr. Clin. Neurophysiol. 105 (1997) 438–450. [20] P. Cicinelli, R. Traversa, A. Bassi, G. Scivoletto, P.M. Rossini, Interhemispheric differences of hand muscle representation in human motor cortex, Muscle Nerve 20 (1997) 535–542. [21] J. Classen, J. Liepert, S.P. Wise, M. Hallett, L.G. Cohen, Rapid plasticity of human cortical movement representation induced by practice, J. Neurophysiol. 79 (1998) 1117–1123.

151

[22] L.G. Cohen, B.J. Roth, J. Nilsson, N. Dang, M. Panizza, S. Bandinelli, W. Friauf, M. Hallett, Effects of coil design on delivery of focal magnetic stimulation. Technical considerations, Electroencephalogr. Clin. Neurophysiol. 75 (1990) 350–357. [23] L.G. Cohen, P. Celnik, A. Pascual-Leone, B. Corwell, L. Falz, J. Dambrosia, M. Honda, N. Sadato, C. Gerloff, M.D. Catala, M. Hallett, Functional relevance of cross-modal plasticity in blind humans, Nature 389 (1997) 180–183. [24] L.G. Cohen, R.A. Weeks, N. Sadato, P. Celnik, K. Ishii, M. Hallett, Period of susceptibility for cross-modal plasticity in the blind, Ann. Neurol. 45 (1999) 451–460. [25] F. Conti, T. Manzoni, The neurotransmitters and postsynaptic actions of callosally projecting neurons, Behav. Brain Res. 64 (1994) 37–53. [26] M.D. Craggs, D.N. Rushton, D.G. Clayton, The stability of the electrical stimulation map of the motor cortex of the anesthetized baboon, Brain 99 (1976) 575–600. [27] M.C. Crair, R.C. Malenka, A critical period for long-term potentiation at thalamocortical synapses, Nature 375 (1995) 325–328. [28] H.R. Dinse, G.H. Recanzone, M.M. Merzenich, Alterations in correlated activity parallel ICMS-induced representational plasticity, Neuroreport 5 (1993) 173–176. [29] J.P. Donoghue, S. Suner, J.N. Sanes, Dynamic organization of primary motor cortex output to target muscles in adult rats. II. Rapid reorganization following motor nerve lesions, Exp. Brain Res. 79 (1990) 492–503. [30] J.P. Donoghue, S. Leibovic, J.N. Sanes, Organization of the forelimb area in squirrel monkey motor cortex: representation of digit, wrist, and elbow muscles, Exp. Brain Res. 89 (1992) 1–19. [31] T. Elbert, C. Pantev, C. Weinbruck, B. Rockstroh, E. Taub, Increased cortical representation of the fingers of the left hand in string players, Science 270 (1995) 305–307. [32] T. Elbert, V. Candia, E. Altenmuller, H. Rau, A. Sterr, B. Rockstroh, C. Pantev, E. Taub, Alteration of digital representations in somatosensory cortex in focal hand dystonia, Neuroreport 9 (1998) 3571– 3575. [33] T. Elbert, A. Sterr, H. Flor, B. Rockstroh, S. Knecht, C. Pantev, C. Wienbruch, E. Taub, Input-increase and input-decrease types of cortical reorganization after upper extremity amputation in humans, Exp. Brain Res. 117 (1997) 161–164. [34] U.T. Eysel, F. Gonzalez-Aguilar, U. Mayer, Time-dependent decrease in the extent of visual deafferentation in the lateral geniculate nucleus of adult cats with small retinal lesions, Exp. Brain Res. 41 (1981) 256–263. [35] H. Flor, T. Elbert, S. Knecht, C. Wienbruch, C. Pantev, N. Birbaumer, W. Larbig, E. Taub, Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation, Nature 375 (1995) 482–484. [36] N. Forss, M. Hietanen, O. Salonen, R. Hari, Modified activation of somatosensory cortical network in patients with right-hemisphere stroke, Brain 122 (1999) 1889–1899. [37] W. Fries, A. Danek, K. Schedtmann, C. Hamburger, Motor recovery following capsular stroke: role of descending pathways from multiple motor areas, Brain 116 (1993) 369–382. [38] R.D. Frostig, E.E. Lieke, Dy. Ts’o, A. Grinvald, Cortical functional architecture and local coupling between neuronal activity and the microcirculation revealed by in vivo high-resolution optical imaging of intrinsic signals, Proc. Natl. Acad. Sci. 87 (1990) 6082–6086. [39] P. Fuhr, L.G. Cohen, B.J. Roth, M. Hallett, Latency of motor evoked potentials to focal transcranial stimulation varies as a function of scalp positions stimulated, Electroencephalogr. Clin. Neurophysiol. 81 (1991) 81–89. [40] K. Fukui, I. Iguchi, A. Kito, Extent of pontine pyramidal tract wallerian degeneration and outcome after supratentorial hemorragic stroke, Stroke 25 (1994) 1207–1210. [41] R.B. Glassmann, Recovery folllowing sensorimotor cortical damage: evoked potentials, brain stimulation and motor control, Exp. Neurol. 33 (1971) 16–29.

152

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154

[42] H.J. 3 rd Gould, Body surface maps in the somatosensory cortex of rabbit, J. Comp. Neurol. 243 (1986) 207–233. [43] A. Heald, D. Bates, N.E.F. Cartlidge, J.M. French, S. Miller, Longitudinal study of central motor conduction time following stroke: 2. Central motor conduction time measured within 72 h after a stroke as a predictor of functional outcome at 12 months, Brain 116 (1993) 1371–1385. [44] D.O. Hebb, The Organization of Behavior, Wiley, New York, 1949. [45] Y. Hirata, S. Kuriki, C. Pantev, Musicians with absolute pitch show distinct neural activities in the auditory cortex, Neuroreport 10 (1999) 999–1002. [46] D.R. Humprey, Representation of movements and muscles within the primate precentral motor cortex: historical and current perspectives, Fed. Proc. 45 (1986) 2687–2699. [47] G.W. Huntley, E.G. Jones, Relationship of intrinsic connections to forelimb movement representations in monkey motor cortex: a correlative anatomic and physiological study, J. Neurophysiol. 66 (1991) 390–413. [48] S. Iglesias, G. Marchal, P. Rioux, V. Beaudouin, A.J. Hauttement, V. de-la Sayette, F. Le Doze, J.M. Derlon, F. Viader, J. Baron, Do changes in oxygen metabolism in the unaffected cerebral hemisphere underlie early neurological recovery after stroke? A PET study, Stroke 27 (1996) 1192–1199. [49] Y. Iwamura, M. Tanaka, M. Sakamoto, O. Hikosaka, Vertical neuronal arrays in the postcentral gyrus signaling active touch: a receptive field study in the conscious monkey, Exp. Brain Res. 58 (1985) 412–420. [50] J.A. Jane, D. Yashon, D.P. Becker, R. Beatty, O. Sugar, The effect of destruction of the corticospinal tract in the human cerebral peduncle upon motor function and involuntary movements. Report of 11 cases, J. Neurosurg. 29 (1968) 581–585. [51] E.G. Jones, Distribution patterns of individual medial lemniscal axons in the ventrobasal complex of the monkey thalamus, J. Comp. Neurol. 215 (1983) 1–16. [52] E.G. Jones, Lack of collateral thalamocortical projections to fields of the first somatic sensory cortex in monkeys, Exp. Brain Res. 52 (1983) 375–384. [53] E.G. Jones, D.P. Friedman, Projection pattern of functional components of thalamic ventrobasal complex on monkey somatosensory cortex, J. Neurophysiol. 48 (1982) 521–544. [54] E.G. Jones, J.D. Coulter, S.H. Hendry, Intracortical connectivity of architectonic fields in the somatic sensory, motor and parietal cortex of monkeys, J. Comp. Neurol. 181 (1978) 291–347. [55] E.G. Jones, D.P. Friedman, S.H. Hendry, Thalamic basis of placeand modality-specific columns in monkey somatosensory cortex: a correlative anatomical and physiological study, J. Neurophysiol. 48 (1982) 545–568. [56] J.H. Kaas, R.J. Nelson, M. Sur, C.S. Lin, M.M. Merzenich, Multiple representations of the body within the primary somatosensory cortex of primates, Science 204 (1979) 521–523. [57] A. Karni, G. Meyer, P. Jezzard, M.M. Adams, R. Turner, L.G. Ungerleider, Functional MRI evidence for adult motor cortex plasticity during motor skill learning, Nature 377 (1995) 155–158. [58] T. Kasai, T. Komiyama, Antagonist inhibition during rest and precontraction, Electroencephalogr. Clin. Neurophysiol. 81 (1991) 427–432. [59] K. Kataoka, T. Hayakawa, K. Yamada, T. Mushiroi, R. Karada, H. Mogami, Neuronal network disturbance after focal ischemia in rat, Stroke 20 (1989) 1226–1235. [60] J.J. Kew, M.C. Ridding, J.C. Rothwell, R.E. Passingham, P.N. Leigh, S. Sooriakumaran, R.S. Frackowiak, D.J. Brooks, Reorganization of cortical blood flow and transcranial magnetic stimulation maps in human subjects after upper limb amputation, J. Neurophysiol. 72 (1994) 2517–2524. [61] S. Knecht, H. Henningsen, C. Hohling, T. Elbert, H. Flor, C. Pantev, E. Taub, Plasticity of plasticity? Changes in the pattern of perceptual correlates of reorganization after amputation, Brain 121 (1998) 717–724.

[62] A. Korvenoja, J. Huttunen, E. Salli, H. Pohjonen, S. Martinkauppi, J.M. Palva, L. Lauronen, J. Virtanen, R.J. Ilmoniemi, H. Aronen, Activation of multiple cortical areas in response to somatosensory stimulation: combined magnetoencephalographic and functional magnetic resonance imaging, Hum. Brain Mapp. 8 (1999) 13–27. [63] T. Kujala, K. Alho, P. Paavilainen, H. Summala, R. Naatanen, Neural plasticity in processing of sound location by the early blind: an event-related potential study, Electroencephalogr. Clin. Neurophysiol. 84 (1992) 469–477. [64] H.C. Kwan, W.A. MacKay, J.T. Murphy, Y.C. Wong, Spatial organization of precentral cortex in awake primates. II. Motor outputs, J. Neurophysiol. 41 (1978) 1120–1131. [65] D.G. Lawrence, H.G. Kuypers, The functional organization of the motor system in the monkey. I. The effects of bilateral pyramidal lesions, Brain 91 (1968) 1–14. [66] D.G. Lawrence, H.G. Kuypers, The functional organization of the motor system in the monkey. II. The effects of lesions of the descending brain-stem pathways, Brain 91 (1968) 15–36. [67] R.N. Lemon, R.B. Muir, G.W. Mantel, The effects upon the activity of hand and forearm muscles of intracortical stimulation in the vicinity of corticomotor neurones in the conscious monkey, Exp. Brain Res. 66 (1987) 621–637. [68] G.L. Lenzi, R.S. Frackowiack, T. Jones, Cerebral oxygen metabolism and blood flow in human cerebral ischaemic infarction, J. Cereb. Blood Metab. 2 (1982) 321–325. [69] W.J. Levy Jr., V.E. Amassian, M. Traad, J. Cadwell, Focal magnetic coil stimulation reveals motor cortical system reorganized in humans after traumatic quadriplegia, Brain Res. 510 (1990) 130–134. [70] J. Liepert, C. Terborg, C. Weiller, Motor plasticity induced by synchronized thumb and foot movements, Exp. Brain Res. 125 (1999) 435–439. [71] Y. Maegaki, Y. Maeoka, S. Ishii, I. Eda, A. Ohtagaki, T. Kitahara, N. Suzuki, K. Yoshino, A. Ieshima, T. Koeda, K. Takeshita, Central motor reorganization in cerebral palsy patients with bilateral cerebral lesions, Pediatr. Res. 45 (1999) 559–567. [72] R. Mariorenzi, F. Zarola, M.D. Caramia, C. Paradiso, P.M. Rossini, Non-invasive evaluation of central motor tract excitability changes following peripheral nerve stimulation in healthy humans, Electroencephalogr. Clin. Neurophysiol. 81 (1991) 90–101. [73] T.M. McKenna, B.L. Whitsel, D.A. Dreyer, Anterior parietal cortical topographic organization in macaque monkey: a reevaluation, J. Neurophysiol. 48 (1982) 289–317. [74] M.M. Merzenich, G.H. Recanzone, W.M. Jenkins, K.A. Grajski, Adaptive mechanisms in cortical networks underlying cortical contributions to learning and nondeclarative memory, Cold Spring Harb. Symp. Quant. Biol. 55 (1990) 873–887. [75] M.M. Merzenich, J.H. Kaas, J. Wall, R.J. Nelson, M. Sur, D. Felleman, Topographic reorganization of somatosensory cortical areas 3b and 1 in adult monkeys following restricted deafferentation, Neuroscience 8 (1983) 33–55. [76] M.H. Merzenich, J.H. Kaas, J.T. Wall, M. Sur, R.J. Nelson, D.J. Felleman, Progression of change following median nerve section in the cortical representation of the hand areas 3b and 1 in adult owl and squirrel monkeys, Neuroscience 10 (1983) 639–665. [77] M.M. Merzenich, R.J. Nelson, M.P. Stryker, M.S. Cynader, A. Schoppmann, J.M. Zook, Somatosensory cortical map changes following digit amputation in adult monkeys, J. Comp. Neurol. 224 (1984) 591–605. [78] R.A. Muller, R.D. Rothermel, M.E. Behen, O. Muzik, P.K. Chakraborty, H. Chugani, Plasticity of motor organization in children and adults, Neuroreport 8 (1997) 3103–3108. [79] H.J. Neville, D.L. Mills, D.S. Lawson, Fractionating language: different neural subsystems with different sensitive periods, Cereb. Cortex. 2 (1992) 244–258. [80] R.J. Nudo, G.W. Milliken, Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys, J. Neurophysiol. 75 (1996) 2144–2149.

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154 [81] M. Oliveri, F. Brighina, V. La Bua, D. Buffa, A. Aloisio, B. Fierro, Reorganization of cortical motor area in prior polio patients, Clin. Neurophysiol. 110 (1999) 806–812. [82] P. Pantano, R. Formisano, M. Ricci, V. Di Piero, U. Sabatini, B. Di Pofi, R. Rossi, L. Bozzao, G.L. Lenzi, Motor recovery after stroke. Morphological and functional brain alterations, Brain 119 (1996) 1849–1857. [83] C. Pantev, R. Oostenveld, A. Engelien, B. Ross, L.E. Roberts, M. Hoke, Increased auditory cortical representation in musicians, Nature 392 (1998) 811–814. [84] A. Pascual-Leone, F. Torres, Plasticity of the sensorimotor cortex representation of the reading finger in Braille readers, Brain 116 (1993) 39–52. [85] A. Pascual-Leone, L.G. Cohen, J.P. Brasil-Neto, J. Valls-Sole, M. Hallett, Differentiation of sensorimotor neuronal structures responsible for induction of motor evoked potentials, attenuation in detection of somatosensory stimuli, and induction of sensation of movement by mapping of optimal current directions, Electroencephalogr. Clin. Neurophysiol. 93 (1994) 230–236. [86] A. Pascual-Leone, E.M. Wassermann, N. Sadato, M. Hallett, The role of reading activity on the modulation of motor cortical outputs to the reading hand in Braille readers, Ann. Neurol. 38 (1995) 910–915. [87] A. Pascual-Leone, D. Nguyet, L.G. Cohen, J.P. Brasil-Neto, A. Cammarota, M. Hallett, Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills, J. Neurophysiol. 74 (1995) 1037–1045. [88] R.L. Paul, H. Goodman, M. Merzenich, Alterations in mechanoreceptor input to Brodmann’s areas 1 and 3 of the postcentral hand area of Macaca mulatta after nerve section and regeneration, Brain Res. 39 (1972) 1–19. [89] W. Penfield, E. Boldrey, Somatic motor and sensory representation in cerebral cortex of man as studied by electrical stimulation, Brain 60 (1937) 389–443. [90] G. Pennisi, G. Rapisarda, R. Bella, V. Calabrese, A. Maertens de Noordhout, P.J. Delwaide, Absence of response to early transcranial magnetic stimulation in ischemic stroke patients. Prognostic value for hand motor recovery, Stroke 30 (1999) 2666–2670. [91] T.P. Pons, J.H. Kaas, Connections of area 2 of somatosensory cortex with the anterior pulvinar and subdivisions of the ventroposterior complex in macaque monkeys, J. Comp. Neurol. 240 (1985) 16–36. [92] T.P. Pons, P.E. Garraghty, D.P. Friedman, M. Mishkin, Physiological evidence for serial processing in somatosensory cortex, Science 237 (1987) 417–420. [93] T.P. Pons, P.E. Garraghty, C.G. Cusick, J.H. Kaas, The somatotopic organization of area 2 in macaque monkeys, J. Comp. Neurol. 241 (1985) 445–466. [94] T.P. Pons, P.E. Garraghty, C.G. Cusick, J.H. Kaas, A sequential representation of the occiput, arm, forearm and hand across the rostrocaudal dimension of areas 1, 2 and 5 in macaque monkeys, Brain Res. 335 (1985) 350–353. [95] C.W. Ponton, M. Don, J.J. Eggermont, M.D. Waring, B. Kwong, A. Masuda, Auditory system plasticity in children after long periods of complete deafness, Neuroreport 8 (1996) 61–65. [96] T.P.S. Powell, V.B. Mountcastle, The cytoarchitecture of the postcentral gyrus of the of the monkey Macaca mulatta, John Hopkins Med. J. 105 (1959) 108–120. [97] J.P. Rauschecker, Mechanisms of visual plasticity: Hebb synapses. NMDA receptors, and beyond, Physiol. Rev. 71 (1991) 587–615. [98] J.P. Rauschecker, Developmental plasticity and memory, Behav. Brain Res. 66 (1995) 7–12. [99] G.H. Recanzone, C.E. Schreiner, M.M. Merzenich, Plasticity in the frequency representation of primary auditory cortex following discrimination training in adult owl monkeys, J. Neurosci. 13 (1993) 87–103. [100] M.C. Ridding, J.C. Rothwell, Afferent input and cortical organisation: a study with magnetic stimulation, Exp. Brain Res. 126 (1999) 536–544.

153

[101] S. Roricht, B.U. Meyer, L. Niehaus, S.A. Brandt, Long-term reorganization of motor cortex outputs after arm amputation, Neurology 53 (1999) 106–111. [102] F. Rosler, B. Roder, M. Heil, E. Hennighausen, Topographic differences of slow event-related brain potentials in blind and sighted adult human subjects during haptic mental rotation, Brain Res. Cogn. Brain Res. 1 (1993) 145–159. [103] S. Rossi, P. Pasqualetti, F. Tecchio, F. Pauri, P.M. Rossini, Corticospinal excitability modulation during mental simulation of wrist movements in human subjects, Neurosci. Lett. 243 (1998) 147–151. [104] P.M. Rossini, S. Rossi, Clinical application of motor evoked potentials, Electroencep. Clin. Neurophysiol. 106 (1998) 180–194. [105] P.M. Rossini, E. Di Stefano, P. Stanzione, Nerve impulse propagation along central and peripheral fast conducting motor and sensory pathways in man, Electroencephalogr. Clin. Neurophysiol. 60 (1985) 320–334. [106] P.M. Rossini, M. Caramia, F. Zarola, Central motor tract propagation in man: studies with non-invasive, unifocal, scalp stimulation, Brain Res. 415 (1987) 211–225. [107] P.M. Rossini, G. Martino, L. Narici, A. Pasquarelli, M. Peresson, V. Pizzella, F. Tecchio, G. Torrioli, G.L. Romani, Short-term brain ‘plasticity’ in humans: transient finger representation changes in sensory cortex somatotopy following ischemic anesthesia, Brain Res. 642 (1994) 169–177. [108] P.M. Rossini, A.T. Barker, A. Berardelli, M.D. Caramia, G. Caruso, R.Q. Cracco, M.R. Dimitrijevic, M. Hallett, Y. Katayama, C.H. Lucking et al., Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee, Electroencephalogr. Clin. Neurophysiol. 91 (1994) 79– 92. [109] P.M. Rossini, A. Berardelli, G. Deuschl, M. Hallet, A. Maertens de Noordhout, W. Paulus, F. Pauri, Applications of magnetic cortical stimulation, Clin. Neurophysiol. Supp 52 (1999) 171–185. [110] P.M. Rossini, S. Rossi, P. Pasqualetti, F. Tecchio, Corticospinal excitability modulation to hand muscles during movement imagery, Cereb. Cortex 9 (1999) 161–167. [111] P.M. Rossini, C. Caltagirone, A. Castriota-Scandberg, P. Cicinelli, C. Del Gratta, M. Demartin, V. Pizzella, R. Traversa, G.L. Romani, Hand motor Cortical area reorganization in stroke: a study with fMRI MEG amt TMS maps, NeuroReport 9 (1998) 2141–2146. [112] P.M. Rossini, F. Tecchio, V. Pizzella, D. Lupoi, E. Cassetta, P. Pasqualetti, G.L. Romani, A. Orlacchio, On the reorganization of sensory hand areas after mono-hemispheric lesion: a functional (MEG) / anatomical (MRI) integrative study, Brain Res. 782 (1998) 153–166. [113] P.M. Rossini, S. Rossi, F. Tecchio, P. Pasqualetti, A. Finazzi-Agro, A. Sabato, Focal brain stimulation in healthy humans: motor maps changes following partial hand sensory deprivation, Neurosci. Lett. 214 (1996) 191–195. [114] P.M. Rossini, F. Tecchio, A. Sabato, A. Finazzi-Agro, P. Pasqualetti, S. Rossi, The role of cutaneous inputs during magnetic transcranial stimulation, Muscle Nerve 19 (1996) 1302–1309. [115] P.M. Rossini, L. Narici, G. Martino, A. Pasquarelli, M. Peresson, V. Pizzella, F. Tecchio, G.L. Romani, Analysis of interhemispheric asymmetries of somatosensory evoked magnetic fields to right and left median nerve stimulation, Electroencephalogr. Clin. Neurophysiol. 91 (1994) 476–482. [116] J.C. Rothwell, P.D. Thompson, B.L. Day, J.P. Dick, T. Kachi, J.M. Cowan, C.D. Marsden, Motor cortex stimulation in intact man. 1. General characteristics of EMG responses in different muscles., Brain 110 (1987) 1173–1190. [117] N. Sadato, A. Pascual-Leone, J. Grafman, V. Ibanez, M.P. Deiber, G. Dold, M. Hallett, Activation of the primary visual cortex by Braille reading in blind subjects, Nature 380 (1996) 526–528. [118] T. Sakamoto, L.L. Porter, H. Asanuma, Long-lasting potentiation

154

[119]

[120]

[121]

[122] [123]

[124]

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132]

P.M. Rossini, F. Pauri / Brain Research Reviews 33 (2000) 131 – 154 of synaptic potentials in the motor cortex produced by stimulation of the sensory cortex in the cat: a basis of motor learning, Brain Res. 413 (1987) 360–364. J.N. Sanes, J. Wang, J.P. Donoghue, Immediate and delayed changes of rat motor cortical output representation with new forelimb configurations, Cereb. Cortex 2 (1992) 141–152. J.N. Sanes, J.P. Donoghue, V. Thangaraj, R.R. Edelman, S. Warach, Shared neural substrates controlling hand movements in human motor cortex, Science 268 (1995) 1775–1777. K.C. Sato, J. Tanji, Digit-muscle responses evoked from multiple intracortical foci in monkey precentral motor cortex, J. Neurophysiol. 62 (1989) 959–970. R.J. Seitz, H.J. Freund, Plasticity of the human motor cortex, Adv. Neurol. 73 (1997) 321–333. R.J. Seitz, G. Schlaug, A. Kleinschmidt, U. Knorr, B. Nebeling, Wirrwa Remote depressions of cerebral metabolism in hemiparetic stroke: topography an relation to motor and somatosensory functions, Hum. Brain Mapp. 1 (1994) 81–100. R.J. Seitz, Y. Huang, U. Knorr, L. Tellmann, H. Herzog, H.J. Freund, Large-scale plasticity of the human motor cortex, Neuroreport 6 (1995) 742–744. B.J. Sessle, M. Wiesendanger, Structural and functional definition of the motor cortex in the monkey (Macaca fascicularis), J. Physiol. (Lond). 323 (1982) 245–265. I. Stepniewska, T.M. Preuss, J.H. Kaas, Architectonics, somatotopic organization, and ipsilateral cortical connections of the primary motor area (M1) of owl monkeys, J. Comp. Neurol. 330 (1993) 238–271. P.L. Strick, J.B. Preston, Two representations of the hand in area 4 of a primate. I. Motor output organization, J. Neurophysiol. 48 (1982) 139–149. M. Sur, J.T. Wall, J.H. Kaas, Modular segregation of functional cell classes within the postcentral somatosensory cortex of monkeys, Science 212 (1981) 1059–1061. M. Sur, J.T. Wall, J.H. Kaas, Modular distribution of neurons with slowly adapting and rapidly adapting responses in area 3b of somatosensory cortex in monkeys, J. Neurophysiol. 51 (1984) 724–744. F. Tecchio, V. Pizzella, P. Pasqualetti, G.L. Romani, P.M. Rossini, SEF waveshape as a marker of neural connectivity: inter-subjective variability and intra-subjective inter-hemispheric similarity (2000) submitted F. Tecchio, G. Bicciolo, E. De Campora, P. Pasqualetti, V. Pizzella, I. Indovina, E. Cassetta, G.L. Romani, P.M. Rossini, Tonotopic cortical changes following stapes substitution in otosclerotic patients: a magnetoencephalographic study, Human Brain Mapping (2000) in press. F. Tecchio, P.M. Rossini, V. Pizzella, E. Cassetta, G.L. Romani, Spatial properties and interhemispheric differences of the sensory

[133]

[134]

[135]

[136]

[137]

[138]

[139]

[140]

[141]

[142]

[143] [144]

[145]

hand cortical representation: a neuromagnetic study, Brain Res. 767 (1997) 100–108. F. Tecchio, P.M. Rossini, V. Pizzella, E. Cassetta, P. Pasqualetti, G.L. Romani, A neuromagnetic normative data set for hemipsheric sensory hand cortical representations and their interhemispheric differences, Brain Res. Protocols 2 (1998) 306–314. R. Traversa, P. Cicinelli, A. Bassi, P.M. Rossini, G. Bernardi, Mapping of motor cortical reorganization after stroke. A brain stimulation study with focal magnetic pulses, Stroke 28 (1997) 110–117. R. Traversa, P. Cicinelli, P. Pasqualetti, M. Filippi, P.M. Rossini, Follow-up of interhemispheric differences of motor evoked potentials from the ‘‘affected’’ and ‘‘unaffected’’ hemisphere in human stroke, Brain Res. 803 (1998) 1–8. A. Turton, S. Wroe, H. Trepte, C. Fraser, R.N. Lemon, Contralateral and ipsilateral EMG responses to transcranial magnetic stimulation during recovery of arm and hand function after stroke, Electroenceph. Clin. Neurophysiol. 41 (1996) 316–328. F. Uhl, P. Franzen, I. Podreka, M. Steiner, L. Deecke, Increased regional cerebral blood flow in inferior occipital cortex and cerebellum of early blind humans, Neurosci. Lett. 150 (1993) 162–164. J.P. Vasama, J.P. Makela, Auditory pathway plasticity in adult humans after unilateral idiopathic sudden sensorineural hearing loss, Hear Res. 87 (1995) 132–140. C. Veraart, A.G. De Volder, M.C. Wanet-Defalque, A. Bol, C. Michel, A.M. Goffinet, Glucose utilization in human visual cortex is abnormally elevated in blindness of early onset but decreased in blindness of late onset, Brain Res. 510 (1990) 115–121. T. Warabi, K. Inoue, H. Noda, S. Murakami, Recovery of voluntary movement in hemiplegic patients. Correlation with degenerative shrinkage of the cerebral peduncles in C.T. images, Brain 113 (1990) 177–189. E.M. Wassermann, L.M. McShane, M. Hallett, L.G. Cohen, Noninvasive mapping of muscle representations in human motor cortex, Electroencephalogr. Clin. Neurophysiol. 85 (1992) 1–8. B. Weder, U. Knorr, H. Herzog, B. Nebeling, A. Kleinschmidt, Y. Huang, H. Steinmetz, H.J. Freund, R.J. Seit, Tactile exploration of shape after subcortical ischaemic infarction studied with PET, Brain 117 (1994) 593–605. S.J. Williamson, L. Kaufman, Evolution of neuromagnetic topographic mapping, Brain Topogr. 3 (1990) 113–127. G. Wunderlich, U. Knorr, H. Herzog, J.C. Kiwit, H.J. Freund, R.J. Seitz, Precentral glioma location determines the displacement of cortical hand representation, Neurosurgery 42 (1998) 18–26. U. Ziemann, M. Hallett, L.G. Cohen, Mechanisms of deafferentation-induced plasticity in human motor cortex, J. Neurosci. 18 (1998) 7000–7007.