Chapter 36 Neurophysiological markers of recovery of function after stroke

Advances in Clinical A'europhysiology (Supplements to Clinical Neurophysiology Vol. 54) Editors: R.C. Reisin, M.R. Nuwer, M. Hallett. C. Medina (Q 2002 Elsevier Science 8. V. All rights reserved.

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Chapter 36

Neurophysiological markers of recovery of function after stroke Paola Cicinelli", Raimondo Traversa'', Massimiliano Oliveria, Maria Giuseppina Palmieri", Maria Maddalena Filippi'" and Paolo Maria Rossini'?' 'Fondazione St. Lucia, IRCCS, 00179 Rome (Italy) bAFaR Ospedale Fatebenefratelli, Isola Tiberina 39, 00186 Rome (Italy) cIRCCS Centro St. Giovanni di Dio - Fatebenefratelli, Rome (Italy) "Neurologia Clinica, Universita Campus Biomedico, Rome (Italy)

Motor recovery and brain plasticity Functional recovery frequently occurs following injuries to the nervous system such as stroke. The extent of recovery is highly variable: while some patients with initial severe hemiparesis may eventually achieve full recovery, others have little or no improvement and remain severely disabled. Although hemiparesis remains a major deficit in patients with chronic stroke, its resolution in about 40% of patients illustrates the potential for functional recovery (Twitchell 1951; Duncan et al. 1992). The question whether clinical recovery of motor function was based upon re-establishment of previously damaged but not destroyed corticospinal connections or to 'plastic' rearrangements of cortical somatotopy in which previously functionally silent or differently operating neuronal pools replace the lost ones is a matter of current investigation (Jenkins and Merzenick 1987; Jacobs and Donoghue 1991; Kaas et al. 1991; Fries et al. 1993; Hess and Donoghue 1994; Seitz and Freund 1997; Sanes and Donoghue 2000). It is now widely ac-

* Correspondence to: Dr. P. Cicinelli, Fondazione Santa Lucia I.R.C.C.S., Via Ardeatina, 306, 00 \79 Rome, Italy. Fax: +39-6-5032097. E-mail: [email protected]

cepted that cortical plasticity has the potential to playa role in recovery, particularly that which occurs over the longer term and that the extent of brain reorganization after the injury is an important factor that influences the recovery (Glassmann 1971; Warabi et al. 1990; Seitz et at. 1994; Hamdy et al. 1998; Liepert 1998,2000; Weiller et al. 1998; Nelles et at. 1999; Yang et al. 1999; Cramer and Bastings 2000). After recovery of lost function, plastic changes with perilesional extension of body parts representations, shift from primary to secondary areas, as well as recruitment of homologous areas of the unaffected hemisphere (UH) ipsilateral to the lesion have been found in experimental animals studies and in human stroke (Chollet et al. 1991; Weiller et al. 1993, 1998; Weder et at. 1994; Binkofski et at. 1996; Caramia et al. 1996, 2000; Turton et al. 1996; Cao et al. 1998; Cohen et al. 1998, 1999; Rossini et al. 1998b; Byrnes et al. 1999; Jones et al. 1999; Pascual-Leone et al. 1999; Cramer et al. 2000; Rossini and Pauri 2000). However, the exact relation between reorganization and restitution of function is unknown and the understanding ofthe principal mechanisms ofmotor plasticity is an important neurobiological goal when looking for better ways to promote motor recovery following brain damage in humans. Identifying and measuring these 'plastic' events will be an

237

important step towards the development of rationally founded treatment strategies in the neurorehabilitation of stroke patients.

Transcranial magnetic stimulation and stroke Among different brain imaging techniques, transcranial magnetic stimulation (TMS) has been used to track short- and long-term changes of motor cortical output in recovering stroke patients (Heald et al. 1993a,b; Catano et al. 1995, 1996; Caramia et al. 1996, 1999; Turton et al. 1996; Rossini 2000; Rossini and Pauri 2000). It can be used to measure various features of motor cortex excitability and corticospinal tract conductivity. These include: (1) the latency and amplitude of motor evoked potentials (MEPs), (2) motor central conduction time (CCT), (3) excitability threshold of motor cortex (ETh), (4), TMS induced inhibitory phenomena, such as the cortical silent period (SP), (4) extension and topography of the excitable area devoted to a given muscle (motor maps) and (5) excitability of the intracortical inhibitory and facilitatory circuits (ICI and :rCF to paired-pulse TMS) (Rossini et al. 1987, 1994; Rothwell et al. 1987; Caramia et al. 1988, 1989, 1991; Hallett 1995,2000; Cicinelli et al. 1997a, 2000; Ahonen et al. 1998; Rossini and Rossi for a review 1998). A number of studies have investigated the ability ofTMS performed early after stroke to predict long-term motor recovery. Most of them agree that the preservation ofMEPs in the affected hand during the stimulation of the contralateral hemisphere with stroke is associated with a good motor outcome regardless the level of the initial clinical deficit, and the absence ofsuch MEPs is usually associated with a poor motor outcome (Heald et al. 1993a,b; Arac et al. 1994; Catano et al. 1995, 1996; Rapisarda et al. 1996; Escudero et al. 1998; Pennisi et al. 1999). Trompetto et al. (2000), in a study performed in acute stroke patients, identified a subgroup ofpatients with absent MEPs on the paretic hand who recovered well. The contralateral MEPs recorded in the normal hand muscles were significantly smaller and with higher threshold than the analogous responses elicited in patients who did not

show any clinical improvement. This finding suggested that the excitability of the UH could be modulated by inhibitory influences from the AH: the more one hemisphere is damaged by stroke, the more the contralateral one becomes hyperexcitable (Traversa et al. 1998; Yang et al. 1999). In addition to the early prognostic application of TMS, the technique could be used for monitoring and quantifying cortical reshaping of the motor maps during post-stroke follow-up (Wassermann et al. 1992; Weiller 1998; Byrnes et al. 1999; Weiller and Rijntjes 1999). Focal magnetic pulses applied to different scalp positions over the motor cortex allow non-invasive mapping of the motor cortex somatotopy in nonnals and in patients with CNS lesions (Cohen et al. 1989; Fuhr et al. 1991; BrasilNeto et al. 1992; Wassermann et al. 1992; Willson et al. 1993; Mortifee et al., 1994; Pascual-Leone et al. 1994, 1995; Cicinelli et al. 1997a). This mapping procedure can identify changes associated with different forms of plasticity (Benecke et al. 1991; Cohen et al. 1991; Topka et al. 1991; Fuhr et al. 1992; Brasil-Neto et al. 1994; Pascual-Leone et al. 1995; Ziemann et al. 1998; Koop et al. 1999). Changes in cortical maps can usually show two main characteristics: (1) enlargement or restriction of the excitable area devoted to a given muscle without any shift of the center of gravity, and/or (2) migration of the map area outside the usual boundaries with a significant shift of the center of gravity. Relatively variable patterns in the topography ofthe cortical hand motor area have been shown in the healthy; however, little intra- and inter-subjects interhemispheric differences of the examined parameters have been found. Therefore, interhemispheric differences of topography in primary sensorimotor cortices are considered a promising measure to follow-up recovery of motor functions following monohemispheric lesions (Cicinelli et al. 1997a; Tecchio et al. 1997). TMS mapping study in stroke Several MEP characteristics and reorganization of the hand motor output by constructing motor maps of the ADM muscle with focal TMS were investigated in 18patients affected by a monohemispheric

238 rior to the coronal plane. TMS intensity used for mapping session was set at 10% above the ETh determined in each patient according to standardized criteria. (Caramia et al. 1988; Rossini et al. 1994) Four consecutive MEPs were gathered from each stimulating site maintaining the optimal coil axis orientation (approximately perpendicular to the presumed location ofthe central sulcus; BrasilNeto et al. 1992). At the 'hot spot' scalp site where MEPs of maximal amplitude and minimal latency were obtained, recordings were repeated after voluntary contraction whenever patient was able to perform it. Patients' neurophysiological findings were compared to those obtained in a control population. In T 1 MEPs were absent in 5 patients (4 'subcortical'; 1 'cortical'). In T2 the reappearance of MEPs from theAH (2 patients: 1 'cortical'; I 'sub-

stroke that occurred 2--4months before enrolment (Cicinelli et al. 1997b; Traversa et al. 1997). Eight patients suffered from a 'cortical' lesion while in the remaining 10 patients the lesion was 'subcortical'. Clinical improvement was evaluated with the Barthel Index for disability (Mahoney and Barthel 1965) and Canadian Neurological Scale (Cote et al. 1986) for neurological status; subscoring for hand functionality was extrapolated from the Canadian Neurological Scale (Hand Motor score). Patients' findings are summarized in Table 1. MEPs were bilaterally recorded from the ADM muscle via focal TMS in the affected hemisphere (AH) and UH at the beginning of (T 1) and after 810 weeks of neurorehabilitation (T2). Eleven positions on each hemiscalp were scanned, covering the pre-central area in a region of 0--8 em lateral to the sagittal plane and 1 em posterior to 8 em anteTABLE I PATIENTS' FINDINGS Age

Lesion

Barthel TI T2

Canadian Scale TI T2

I 2 3 4 5 6 7 8

66 66 75 64 77 63 63 58

Subcortical right Cortical right Subcortical left Subcortical left Cortical left Subcortical left Subcortical left Subcortical left

15 10 10 40 25 45 15 35

45 50 35 100 65 65 40 95

0 I 0 0.5 0.5 0.5 0.5 I

0 1.5 0 I 1.5 I I 1

9 10 II 12

80 59 56 62

Cortical left Cortical left Cortical right Subcortical left

45 10 70 65

65 60 90 85

0.5 0 0.5 0

1 I I 0.5

13

57

Subcortical left

70

85

0

14 15

65 60

Cortical left Subcortical left

15 40

55 65

0.5 0

a

16

62

Cortical left

50

75

0

0.5

17 18

38 30

Subcortical left Cortical left

60 95

85 100

0 I

0.5 1.5

Mean ± S.D.

61.1 ±12

39.7 ±25

71.6 ±21

0.3 ± 0.3

0.8 ± 0.5

0.5

Anomalous 'hot spot' TI T2 DH AH DH

Eth AH

* *

* *

No MEP

No MEP

* *

* No MEP No MEP

*

*

No MEP

DH

50% 80% 55% 60% 50% 75% 40% 70% 40% 40% 40% 75% 35% 50% 45% 100% 50% 75% 55% 55% 40% 50% 45% 100% 40%

*

No MEP No MEP

* No MEP

AH

100%

40% 55% 30% 100% 30% 100%

*

* *

30% 45%

45% 48%

42.2 71.0 ± 7.9 ± 21.7

239

cortical') was correlated with a consistent improvement of clinical scores (Table 1). MEP ETh of the AH was significantly higher in stroke patients than in controls and in the UH (p < 0.001); the absolute as well as the interhemispheric difference of ETh values were abnormal in 10 patients: 8 'subcortical' and 2 'cortical' (41.6% vs. 16%; p < 0.05) (Table 1). In T 1, the extension of cortical output to the paretic ADM muscle (evaluated as the number of excitable scalp sites) was restricted compared with the normal side (4.5 ± 1.7 in UH and 2.2 ± 1.7 in AH; p < 0.05) and in T2, a significant enlargement (3.3 ± 2.2;p < 0.05) was observed in the AH of 10 patients (Fig. 1). When the topography of the motor maps was analyzed, anomalous 'hot spot'

sites (defined as scalp positions from which TMS never elicits MEPs in normals) were found both on the UH and the AH, more frequently in T2 (8 patients) than in TI (3 patients) and in 'cortical' (2/3 in Tl and 6/8 in T2) more than in 'subcortical' lesions (Table 1). It might represent a neurophysiological marker of plastic rearrangement of cortical output relying on the activation of secondary motor areas and involving both hemispheres. In T 1, the relaxed and contracted MEP amplitudes were significantly reduced from the AH (p < 0.00 I). The amplitude ofcontracted MEPs were larger than normal in the UH at a nearly significant level (p = 0.06). In T2, relaxed-MEP amplitudes from the AH nearly doubled with respect to TI, while the con-

T1

T2

Unaffected

Affected

Unaffected

• •

••• •

•.'

•

•••• ••

0-20%

•

•

21-50%

•

51-80%

•

80-100%

I

• • • ..'

•

Controls

Left

'

Right

..• ••.'

Fig. I. ADM muscle maps in a population of stroke patients in TI and T2 (upper part) and in a population of normal subjects (lower part). In TI, motor maps of the AH were significantly reduced when compared to the UH and to the controls. In T2, a significant enlargement of the ADM maps was found in the AH and a reshaping of the hand somatotopical organization was observed in both hemispheres of stroke patients suggesting that bi-hemispheric plastic changes have occurred.

240

tracted-MEP amplitudes showed an inverse behaviour in the two hemispheres: they were decreasing in the DH and increasing in the AH. The significant interhemispheric differences observed in T 1 (p < 0.0001) tended back to a normal balance in T2 ('balancing') (Traversa et al. 1998). The contracted MEP amplitude in the DH showed a clear and significant decrement (p = 0.013, Wilcoxon test) only in patients with contracted MEP amplitudes increment in the AH. This 'balancing' was correlated with a good clinical outcome (p < 0.002). Alternatively, in patients with no MEP in the AH both in T 1 and in T2, hand function recovered poorly and contracted MEPs from the UH further increased in amplitude during the second session (= 'unbalancing'). In the AH, MEP latencies were significantly delayed and the CCT was prolonged both in TI and in T2. The cortical SP of the AH was frankly prolonged in T I, and the interhemispheric difference of SP duration was about 9 times larger than in controls (p < 0.001). In T2, the SP duration decreased from the AH, and the interhemispheric differences reduced. Barthel Index (p < 0.001) and Canadian Neurological Scale (p < 0.001) scores improved between T 1 and T2. When considering the clinical and neurophysiological correlation, a significant linkage was found between the improvement of the Hand Motor score in T2 and changes ofMEP amplitude (p < 0.002), shortening of SP duration (p < 0.004) and the enlargement of the hand motor areas (p < 0.005). A neurophysiological negative predictive pattern for recovery of arm-hand functionality is mainly related to the absence of MEPs and the presence of an anomalous 'hot spot'. The latter observation is more frequent in 'cortical' lesions and probably reflects the involvement of neuronal pools remote from the primary motor cortex and seems to be correlated with poorer motor outcome with respect to those cases in whom the 'usual' sites are excitable. Between 2 and 4 months following a monohemispheric stroke the motor output from brain motor areas to the hand is still undergoing a remarkable reorganization functionally related to motor recovery. Patients' clinical outcome correlated well with the improvement ofthe neurophysi-

ological parameters and the enlargement of the excitable brain area in the stroke hemisphere. ETh and extension of the maps were more altered in subcortical than in cortical lesions only in T I; this could probably be ascribed to the larger number of densely packed fibers destroyed by the subcortical lesion and to a less efficient and slower 'plastic' reorganization. An increased cortical motor output from the DH was present in T I. It significantly decreased in T2 in combination with an increasedAH output. This 'balancing' phenomenon could either due to transcallosal inhibition better exerted by the AH in recovering T2 than in T I or to the fact that the increased use ofthe unaffected hand would recede with improved use ofthe affected hand in the frame of 'use dependent' adaptation. The progressive balancing of the hemispheric output during voluntary contraction turned out to be one of the neurophysiological markers of good clinical recovery. It clearly emerged that interhemispheric differences of the examined items yield significantly more abnormalities than their absolute values. Therefore, the analysis of interhemispheric asymmetries of the neurophysiological parameters beside their absolute values, could significantly enlarge the diagnostic-prognostic yield.

Brain imaging methods: an integrated approach A number of human brain mapping methods have been used to investigate the brain processes that contribute to stroke recovery. (Lenzi et al. 1982; Williamson et al. 1990; Hari et al. 1993; Yousry et al. 1995; Derlon et al. 1996; Beinsteiner et al. 1997; Cao et al. 1998; Rossini et al. 1998b; Caramia et al. 2000; Staines et al. 2001). 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 (fMRl). Another group of techniques analyses electromagnetic properties of the brain neurons, which can be assessed via modern types of electroencephalography (EEG) and magnetoencephalography (MEG). Neuroimaging

241

studies with PET, fMRI and transcranial doppler (TCD) have traced the evolution of brain motor output following stroke suggesting that a dynamic, bihemispheric reorganization occurs during recovery of paretic hands (Staines et al. 2001). When results are considered together, they have complementary strength and insights into the biological basis of recovery. TMS mapping, MEG and jMRJ study in stroke

Attempts for combining different methods of functional brain imaging in the same subjects have been previously done showing that complementary useful information can be obtained (Beisteiner et al. 1997). The anatomo-functionality of the sensorimotor areas devoted to the hand by means of a multimodal approach including TMS mapping of a hand muscle, MEG and tMRI was investigated in a patient affected by right hemiparesis with excellent motor recovery and persisting motor aphasia 12 months from an ischaemic stroke in the MCA territory (Rossini et al. 1998c). Focal TMS was performed in a mapping protocol in which 19 positions on each hemiscalp were scanned and motor maps of the opponens muscle (OP) in the paretic and healthy side were obtained. In the MEG study, 25 measuring sites were positioned over the scalp in an area of about 180 em? corresponding to the rolandic region. The left and right little finger. thumb and median nerve at wrist were independently stimulated by 0.2 ms electric pulses. Somatosensory evoked fields (SEFs) (the 'hand extension' and its relative position) were calculated in each hemisphere and compared with the normative limits (Tecchio et al. 1997). In the fMRI study, the sequential opposition of the thumb to the other four fingers was adopted as a task to identify the extension and location of haemodynamic changes of the activated hand cortical areas. The resulting statistical maps were fused with the anatomical data after appropriate co-registration of the functional images with the anatomical ones (Woods et al. 1992). The three methods offunctional imaging showed a similar and concordant shift of the sensorimotor hand areas topography in the AH: a posterior and

lateral shift in the AH with respect to the UH was found in TMS mapping, MEG and tMRI study. In the AH, the ETh to TMS was normal (51%) and the latency of hot-spot MEPs (28.2 ms) and of the N20m (26 ms) was significantly delayed. The extension ofADM maps to TMS, the 'hand extension' in MEG study and the extension of the activated areas in the tMRI evaluation was larger in the AH than in the UB. These results support the idea that TMS, MEG and tMRI rely on similar functional substrates; at least for hand control a good correlation and complementary information from these different methods could be obtained. Multimodal techniques for functional brain evaluation, therefore, might be of significant help in studying patients with monohemispheric lesions (i.e. stroke) with the aim of testing the presence and amount of 'plasticity' phenomena underlying partial or total clinical recovery of hand function (Rossini et al. 1998c).

Rehabilitation and recovery In addition to injury-related reorganization there is a second kind of process, use-dependent cortical reorganization that results from the increased use of body parts in behaviourally relevant task. It is still unclear whether cortical reorganization following stroke is due to a spontaneous recovery process or to rehabilitation therapy. However, rehabilitation procedures are considered to be the trigger for use-dependent reorganization of the lesioned brain area(s) (Hummelshein and Hauptmann 1995; Pascual-Leone et al. 1995; Hauptmann and Hummelshein 1996; Nudo et al. 1996a,b; Liepert et al. 1998; 2000; Cohen et al. 1999; Jones et al. 1999; Koop et al. 1999). Different physiotherapeutic approaches are nowadays available for the functional rehabilitation of stroke patients and utilise techniques which are intended to have an effect either at a 'central' or at a 'peripheral' level. Central facilitation techniques mainly act at a cortical level by activating brain mechanisms of perceptual awareness and purposeful behaviour (cortical facilitation) (Affolter and Striker 1980; Perfetti 1986). Peripheral facilitatory techniques utilise strategies

242 of motor control impinging upon the spinal level and are based on the Sherrington (1906) hypothesis of reciprocal innervation (Bobath 1970). Neurophysiological follow-up during post-stroke rehabilitation A follow-up of neurophysiological markers of corticospinal tracts and functionality related to motor performances and skills in daily living activities was performed for a 4-month period in a group of 20 post-acute stroke in-patients during rehabilitation treatment. We tried to find out whether the analysis of neurophysiological parameters as tested by TMS could identify objective boundaries separating two neurorehabilitation treatments with different theoretical basis (i.e. 'peripheral' vs. 'central' effect) (Traversa et al. 2000). Eleven patients were affected by right hemispheric lesions (9 ischaemic, 2 haemorragic; 6 cortical, 5 subcortical) and 9 were affected by left hemispheric lesion (6 ischaemic, 3 haemorragic; 3 cortical, 6 subcortical). Patients were grouped according to the neurorehabilitation treatment in which they were randomly enrolled: the first group (10 patients) followed a rehabilitation method based upon the 'Perfetti technique' (1986) ('central' or 'cognitive' approach), the other (10 patients) underwent treatment according to Bobath's 'peripheral' approach (1970). At enrolment, the two groups were equivalent in age and neurological status. MEPs to TMS were recorded from upper limb muscles of the paretic and non-paretic side: deltoid (DEL), extensor digitorum communis (ECD), opponens pollicis (OP) and abductor digiti minimi (ADM). Neurophysiological data were recorded in five different sessions: TO (about 1 month from the stroke and corresponding to the start ofthe rehabilitation treatment), T1 (15 days), T2 (42 days), T3 (90 days) and T4 (120 days) from TO. All recordings were taken in the rest condition and during selective contraction of the target muscles (whenever possible). Patients received a full neurological examination at each recording session and their status was scored with the Canadian Neurological Scale (Cote et al. 1986) with the extrapolation ofthe hand items (Hand Motor score), and the Barthel Index

(Mahoney and Barthel 1965). A series of neurophysiological measurements were made. At TO (baseline), all neurophysiological characteristics of the AH showed a significant difference vs. the UR. During the follow-up, a progressive improvement of the tested neurophysiological parameters was observed and are reported in Table 2. The statistically significant changes all took place between TO and T2, corresponding to a period 12.5 months after the stroke. Excitability threshold ETh was significantly and progressively decreasing in the AH (p < 0.001 between TO and T4); the decrement toward normality began to be significant at T2 (0.034) and continued progressively up to T4 (Fig. 2). However, a permanent impairment of the cortical excitability in the stroke hemisphere was present and a significant interhemispheric asymmetry was still present in T4 (t-test,p < 0.001). The Perfetti and Bobath groups did not show any significant differences in all the examined measures except for the SP duration. For this measure, the rehabilitation/technique factor seemed to playa significant role; Perfetti's method decreased the SP more rapidly than Bobath's method and the changes from TO and T2 were more significant in Perfetti than in Bobath patients (F-test; p =0.001). Clinical scores Barthel Index and Canadian Neurological Scale scores progressively improved during the rehabilitation cycle in all patients (p < 0.001 between TO and T4), without any differences between Perfetti and Bobath treated patients. Focusing on the Hand Motor score, the most significant changes were present between TO and T2. The clinical and functional outcome and the neurophysiological markers improved in parallel in both groups, suggesting that throughout the follow-up, the two rehabilitation methods tended to produce similar effects, even if the Perfetti rehabilitation technique facilitated a faster recovery of central inhibition. This could be assumed to be dependent on the specific approach of the cognitive method aimed to a corticalization of the central movement imagery on patients. This outcome was

243 Excitability 00 -

o~

t>

-H

threshold

80

00

,...:-

"" +1

70

----

?F 60

EI

~

-AH

o UH TO

T1

T2

T3

T4

Fig. 2. Follow-up of ADM muscle ETh from the AH and UH in stroke patients.

voo;

,..;0 -

vo

+1

C> ~

~ +1

O\r-:OO--:N~O\C;OO\C;

OONr-=Nr-:Nr-:-~"'­ ~+I~-H~-H~+I~+I

achieved without differences in the time course of ETh improvement confirming the idea that the SP originates from inhibitory mechanisms. The most clinical/neurophysiological improvement was seen between TO and T2 recording sessions (1 to 2.5 months from the stroke) suggesting this period as the one in which plastic changes of cortical motor areas are mainly active. This finding supports the idea that the rehabilitation procedures would be concentrated in the first 80 days following stroke (Traversa et a1. 2000).

Conclusions TMS performed in subacute stroke patients and during follow-up could provide some insights into the understanding of mechanisms involved in the recovery of motor function following the stroke. In the TMS mapping study, clinical recovery was found to be related to the improvement of several MEP measures including the enlargement of the motor cortical output area to the paretic muscles, the increased MEP amplitude, the shortened MEP latency and CCT, the decreased SP duration (Cicinelli et a1. 1997a,b; Traversa et a1. 1997). Interhemispheric asymmetries of MEPs might represent a powerful neurophysiological indicator ofmotor dysfunction and could be proposed as more useful for a diagnostic/prognostic tool (Cicinelli et a1. 1997a,b).

244

An adjunctive neurophysiological indicator of a good motor outcome derived from the observation that the recovery of the excitability of the AH with a progressive 'balancing' of the UH hyperresponsiveness, was combined with clinical improvement of disability and neurological scores (Traversa et al. 1998). Negative neurophysiological findings correlated with a poor clinical recovery resulted from the absence of MEPs and the presence of 'anomalous' hot spots. The increased excitability and the further hyperexcitability of the UH was also correlated with a poor recovery of the hand functionality ('unbalancing') (Cicinelli et al., 1997b; Traversa et al. 1997, 1998). An attempt to combine different methods offunctional brain imaging in the investigation ofthe brain processes that contribute to stroke recovery has shown that complementary useful information can be obtained (Rossini et al. 1998c). Combining the findings ofTMS mapping with functional imaging results (MEG and fMRI) will provide a better understanding ofplastic changes in the stroke-affected hemisphere and their relationship to the recovery. The rearrangement of motor cortical output was found still operating after 5 months from the stroke and was correlated with a clinical improvement in disability and neurological scores in a population of stroke patients that underwent the rehabilitative treatment. The best part of the clinical/neurophysiological outcome was achieved in the first 80 days (2.5 months) following the stroke, suggesting that plastic rearrangements of motor cortical areas are mainly active in this period and that most of the rehabilitation treatment might be concentrated in that time (Traversa et al. 2000). The neural mechanisms underlying the functional recovery induced by certain rehabilitative procedures following damage to the CNS in humans are not completely understood yet. The possibility to find out whether different neurorehabilitation procedures could induce specific pattern offunctional recovery is still a matter ofdebate. Among several physiotherapeutic approaches that are nowadays available for the rehabilitation of stroke patients, none of them has been proved to be superior to the others in promoting motor recovery oflost function. TMS could

be employed in identifying specific different profiles of motor system modifications following different neurorehabilitation strategies. A specific neurophysiological modification has been demonstrated in our population of stroke patients treated with two different neurorehabilitation procedures, namely the Perfetti and the Bobath technique. The Perfetti technique has been found to induce a faster recovery of central inhibition than the Bobath technique as revealed by the earlier SP duration shortening during the TMS follow-up. It suggests that the specific strategy of neurorehabilitation may implicate a different neurophysiological profile. To substantiate and optimize physiotherapeutic techniques, further investigations are required to reveal the functional value of their application.

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