Hand Function and Motor Cortical Output Poststroke: Are They Related?

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ORIGINAL ARTICLE

Hand Function and Motor Cortical Output Poststroke: Are They Related? Brenda J. Brouwer, PhD, Kim Schryburt-Brown, MSc ABSTRACT. Brouwer BJ, Schryburt-Brown K. Hand function and motor cortical output poststroke: are they related? Arch Phys Med Rehabil 2006;87:627-34. Objectives: To characterize hand function and cortical excitability in chronic and subacute stages of stroke recovery and to describe the relations between these measures. Design: Observational, case-control, and cohort pre-post inpatient rehabilitation. Setting: Motor performance laboratory. Participants: Fourteen community-living chronic and 14 subacute inpatient stroke survivors volunteered. Fourteen similarly aged healthy subjects served as a control group. Interventions: Not applicable. Main Outcome Measures: Finger tapping, peg placing, and strength were measured as indicators of hand function. The amplitude and latency of motor-evoked potentials (MEPs) and the duration of the silent period in the first dorsal interosseous muscle elicited by transcranial magnetic stimulation (TMS) reflected the integrity of excitatory and inhibitory cortical circuits. Results: Diminished hand function, small MEPs, and prolonged silent-period durations were evident in stroke compared with control subjects. Longer MEP latencies and smaller amplitudes distinguished subacute from chronic stroke. Side-toside asymmetries were greatest in the subacute group for all TMS outcomes, although this lessened over time based on the subsample retested at discharge. Greater side-to-side MEP amplitude symmetry and lower motor threshold (lesioned side) were associated with better hand function in subacute and chronic stroke, respectively. Conclusions: Cortical excitability is an important determinant of hand function poststroke and evolves with the time elapsed since the stroke event. The unique neural correlates of hand function evident in subacute and chronic stroke may reflect different phases of neuromuscular recovery. Key Words: Evoked potentials, motor; Hand; Magnetics; Rehabilitation; Stroke. © 2006 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

From the Motor Performance Laboratory, School of Rehabilitation Therapy, Queen’s University, Kingston, ON, Canada. Supported by the Heart and Stroke Foundation of Ontario (grant no. NA 4839) and the Natural Sciences and Engineering Research Council (postgraduate scholarship). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Brenda J. Brouwer, PhD, School of Rehabilitation Therapy, Queen’s University, 31 George St, Kingston, ON K7L 3N6, Canada, e-mail: brouwerb@ post.queensu.ca. 0003-9993/06/8705-10333$32.00/0 doi:10.1016/j.apmr.2006.02.006

RANSCRANIAL MAGNETIC stimulation (TMS) of the T motor cortex has shown changes in cortical organization, excitability, and output after stroke providing insight into

mechanisms of motor recovery.1-8 Several studies report that the presence of motor-evoked potentials (MEPs)8-13 and normal central conduction velocity2,14 early in the acute stage are independently good predictors of recovery. Whether this translates into coordinated functional use of muscle groups, however, remains unclear because recovery is typically dichotomized as good or poor based on clinical impression or a criterion score on a global assessment of physical performance.2,6,10,13-16 Clinical scales often lack sensitivity to sensorimotor function,17 and categorization precludes detailed exploration of the relation between TMS responses and physical ability. TMS activates motor cortical cells transynaptically to evoke volleys via the fast corticospinal tract, which projects most strongly to intrinsic hand muscles.18,19 It follows that the integrity of the neural elements mediating the TMS responses may be most directly reflected by measures of target muscle output and manual performance. In healthy subjects, cortical excitability and MEP amplitude directly correlate with muscle strength, finger tapping, and peg placing.20,21 In chronic stroke, associations between MEP amplitude asymmetry (affected side, unaffected side) and grip strength show correspondence between motor cortical output and motor recovery.4 The relation between neurophysiologic markers and hand function in the earlier stages of recovery are not well described apart from the similarity in time course of changes in MEP characteristics and clinical improvement.6 Studies of inhibitory circuits performed by using TMS have shown pronounced suppression of muscle activation (silent period) during the acute stage1,22,23 that normalizes within several months in accompaniment of better clinical outcomes but not necessarily changes in MEP characteristics.1,22,24 The time course of specific TMS outcome measures after stroke varies, which suggests that their respective associations with motor function may change depending on the stage of recovery. This study characterized hand function in terms of finemotor control and TMS responses in subacute and chronic stages of stroke recovery in comparison to healthy subjects to identify distinguishing neurophysiologic features and the neural correlates of hand function. A subsample of the subacute group was retested at discharge from rehabilitation to determine the extent to which functional and neurophysiologic changes parallel each other. This information is important to identify markers compatible with recovery and to better understand the mechanisms of neuromuscular change. METHODS Participants Twenty-eight first-ever stroke survivors with unilateral hemispheric lesions resulting in impaired upper extremity and hand function participated; none had apraxia or receptive aphasia. Upper-limb impairment and function was evaluated by Arch Phys Med Rehabil Vol 87, May 2006

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using 3 subscales of the Motor Assessment Scale (MAS), which collectively included 17 physical task items involving the shoulder, elbow, and hand.25 Items were scored from 0 (no muscle activity) to 4 (normal movement pattern) and summed to provide a total score out of 68. Fourteen inpatients of a stroke rehabilitation unit less than 2 months poststroke formed the subacute group, and subjects in the chronic group were community dwelling, having experienced their stroke 6 months or more before the study. All in the chronic group had been recipients of inpatient rehabilitation early poststroke. In 14 subjects, the lesion involved the left hemisphere and in 14 the right hemisphere after either ischemic (n⫽20) or hemorrhagic (n⫽8) strokes with subcortical (n⫽12) or mixed cortical-subcortical involvement (n⫽16). Chart records indicated that lesions were mostly in the middle cerebral artery territory. Fourteen similarly aged, right-handed, community-dwelling, healthy volunteers formed a comparison group. The participant characteristics are summarized in table 1. Subjects were screened to ensure they had no contraindication for TMS (eg, stent, intracranial metal implant, cardiac pacemaker), and all provided informed consent. The study and

procedures were approved by the research ethics board of the university and affiliated teaching hospitals. Hand Function To examine fine-motor ability, 3 tests of hand function were completed for each hand while subjects were seated; the order was determined by card draw (details in Brouwer et al20). A tapping task required subjects (eyes closed) to tap a single keyboard key with their index finger as many times as possible in three 15-second trials. The total number of key presses was recorded. As an indicator of manipulative skill, subjects retrieved metal pegs one at a time from a well and placed them into holes arranged vertically on a Purdue pegboard.a Three 30-second trials were performed, and the total number of pegs placed was recorded.26 Strength of the first dorsal interosseous (FDI) muscle was measured with the hand flat on a table and the wrist secured in a neutral position while subjects were instructed to slowly push as hard as they could with their index finger against a metal bar instrumented with a strain gauge. The isometric maximal voluntary contraction (MVC) force gener-

Table 1: Subject Characteristics Subject

Group

Sex

Age (y)

Months Since Stroke

1 2 3 4 5 6 7* 8 9* 10 11 12* 13* 14 Group summary

SA SA SA SA SA SA SA SA SA SA SA SA SA SA SA

M M F M M F F M F M F F F F 6M/8F

77 73 69 67 64 59 32 65 68 80 63 82 71 77 67⫾12

0.5 2.0 1.5 2.0 1.2 0.8 1.5 1.8 1.0 1.7 1.2 1.5 1.0 1.4 1.4⫾0.4

15 16 17 18 19 20 21 22 23 24 25 26 27 28 Group summary

Chr Chr Chr Chr Chr Chr Chr Chr Chr Chr Chr Chr Chr Chr Chr

M M F F M M F M F F F M F F 6M/8F

67 68 61 45 66 67 59 53 75 83 61 60 20 80 62⫾16

17 135 108 72 132 52 45 41 23 54 109 9 14 540 96⫾135

Group summary

Control

7M/7F

65⫾14

Lesion Side

Right Right Right Left Left Left Right Left Left Left Right Left Right Left 6 right 8 left Right Left Right Left Right Right Left Left Right Right Right Right Left Left 8 right 6 left

MAS Score†

Type of Stroke

19 18 23 7 59 19 0 0 0 45 39 44 10 60 24⫾21

Ischemic, mixed, MCA Hemorrhagic subcortical, BG Ischemic, mixed, MCA Ischemic, mixed, MCA Ischemic, mixed, MCA Ischemic, subcortical, IC Ischemic, mixed, MCA Hemorrhagic, subcortical, thalamus Ischemic, mixed, MCA Ischemic, subcortical, lacunar Ischemic, mixed, MCA Hemorrhagic, subcortical, BG Ischemic, mixed, MCA Ischemic, subcortical, BG

67 48 51 29 28 59 62 19 63 11 18 61 68 56 46⫾20

Ischemic, mixed, MCA Ischemic, subcortical, BG Ischemic, mixed, MCA Ischemic, mixed, MCA Ischemic, mixed, MCA Hemorrhagic, subcortical, BG Ischemic, subcortical, IC Ischemic, subcortical, lacunar Ischemic, mixed, MCA Hemorrhagic, subcortical, BG Hemorrhagic, mixed Hemorrhagic, subcortical Hemorrhagic, subcortical, BG Ischemic, mixed, MCA

NOTE. Summary values are mean ⫾ standard deviation. Abbreviations: BG, basal ganglia; Chr, chronic; F, female; IC, internal capsule; M, male; MCA, middle cerebral artery; mixed, cortical-subcortical stroke; SA, subacute. *Those not retested at discharge. † MAS upper-extremity subscale score (max, 68).

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ated over 3 trials was recorded. Rest periods between trials were provided to avoid fatigue. Neurophysiologic Measures Subjects were seated comfortably while disposable adhesive Ag-AgCl disk electrodes were attached to the skin overlying the FDI muscle of the left and right hands in a belly-tendon montage referenced to a ground electrode. Electromyographic signals were filtered (range, 10Hz–1kHz), amplified (1000 times), and digitized at 4kHz per channel by using a commercial analog-to-digital interface and software.b Signals were also displayed on an oscilloscope for continuous monitoring. MEPs were recorded in response to single TMSc delivered through a figure of 8 coil (external wing diameter, 8cm) placed on the scalp overlying the motor cortex of the left and right hemisphere in turn (random order). The optimal scalp position for eliciting MEPs in the contralateral FDI muscle was located and motor threshold determined as the lowest stimulus intensity required to elicit 5 MEPs at least 50␮V in amplitude after 10 consecutive stimuli.27 Ten suprathreshold stimuli (20% above motor threshold) were then delivered at 3- to 5-second intervals while subjects maintained a slight isometric contraction or in cases of limited ability to activate FDI (n⫽5) subjects contracted the homologous muscle as a means of facilitation.2,6,8,12 A target force corresponding to 20% of MVC was displayed as well as the magnitude of the index finger abduction force to encourage activation; rest periods between subsequent stimuli were provided as needed to avoid fatigue. The MEP amplitude (peak-to-peak) and latency were determined from the average trace. The inhibitory effects induced by TMS were studied from the silent period, a transitory reduction in electromyographic activity during muscle activation after cortical stimulation.28 The early part of the silent period is because of refractoriness and recurrent inhibition of spinal motoneurons, and the latter portion (⬎50ms) involves intracortical inhibitory circuits likely mediated through GABABergic action (see Seibner and Rothwell19 for review). The duration of the silent period was measured from the start of the MEP to resumption of electromyographic activity. Ten subjects in the subacute group were retested at discharge, which occurred 2 to 7 weeks after the initial assessment. Statistical Analysis Shapiro-Wilks tests of normality ensured the appropriateness of applying parametric statistics. We used t tests to determine whether differences in association with hand dominance were evident in control subjects, which indicated whether this factor needed to be considered in stroke. None existed for any of the neurophysiologic measures (P⬎.244). For all subsequent analyses, we aligned data associated with the nonparetic hand in stroke with the right hand of controls and the paretic with the left hand. Analyses of variance (ANOVAs) with 1 between-subject factor (group) and 1 within-subject factor (side) were performed to identify main effects and interactions between factors for all dependent measures. Tukey post hoc analyses were performed as appropriate to determine between which groups differences lay. One-way ANOVAs were conducted to explore group differences in the side-to-side asymmetry—paretic (left) ⫺ nonparetic (right)/paretic (left) ⫹ nonparetic (right)—for each outcome. Pearson correlation coefficients were calculated to detect associations between measures of hand function and TMS outcomes. Changes over the period of inpatient rehabilitation were analyzed by using a 2-factor (time, side) withinsubject ANOVA.

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All analyses were performed by using the SPSS,d adopting a P value of .05. Descriptive statistics reported are in all cases means ⫾1 standard deviation (SD). RESULTS All subjects tolerated the procedures well except for 1 subacute stroke survivor who reported a severe headache after TMS. Hand Function A main effect of group evident for all tests of hand function (P⬍.001) confirmed that the control group outperformed both stroke groups in tapping, peg-placing ability, and strength. Chronic and subacute groups performed similarly (Pⱖ.094), although the chronic group showed less impairment of the arm and hand (MAS score: 45.7⫾20.3 and 24.5⫾21.3, respectively; P⫽.012). Five subjects (2 chronic, 3 subacute) were unable to do any of the tasks of hand function with their paretic hand, and an additional 2 subacute subjects could tap and generate low FDI force but were unable to place pegs. Not surprisingly, performance on the nonparetic (right) side was superior to the paretic or left side for all measures of hand function (P⬍.001). Post hoc analysis revealed that in control subjects only, FDI strength was comparable between sides (P⫽.44); otherwise, performance was better on the dominant right side. Interactions between group and side (Pⱕ.002) reflected the more pronounced interlimb asymmetries in tapping, peg placing, and strength in stroke groups. Performance on the paretic side averaged between 20% and 68% of that achieved contralaterally, thus far exceeding the differences between dominant and nondominant limbs in control subjects. Furthermore, tapping (P⬍.05) and peg-placing (P⬍.001) performance on the nonparetic side was poorer than that observed from either limb of control subjects; FDI strength on the nonparetic side, however, was comparable with controls (P⬎.11). The data are summarized in table 2. Neurophysiologic Indicators Motor threshold for both hemispheres was higher in chronic and subacute stroke than in control subjects accounting for the observed main effect of group (P⬍.001). Side was also important (P⬍.001), with abnormally higher motor thresholds on the lesioned side thus contributing to marked hemispheric asymmetries in both stroke groups, the group-side interaction (P⬍.001) reflecting interhemispheric symmetry in control subjects. In 2 chronic and 3 subacute stroke survivors, TMS failed to produce MEPs despite maximum intensity stimulation. In these same subjects with subacute stroke, their motor threshold on the intact side exceeded 2 SDs above the mean for controls; this was not the case for those with chronic stroke. In the remaining subjects, suprathreshold stimulation produced MEPs differing in their characteristics (amplitude, latency) by group (P⬍.001) and side (P⬍.001), although these factors interacted to a significant degree (P⬍.03). Post hoc analyses revealed that although MEPs from the paretic FDI were smaller in chronic (P⬍.025) and subacute (P⬍.001) groups compared with either side in controls, there were significant interlimb asymmetries in stroke because MEPs on the nonparetic side were nearly 2 and 6 times larger in chronic (P⬍.02) and subacute stroke (P⬍.001), respectively. Also, MEPs recorded from the paretic FDI were larger in chronic than subacute stroke (Tukey, P⬍.03). The corresponding latencies were normal except for the paretic FDI in subacute stroke, which were prolonged by 4 to 5ms compared with chronic (P⬍.005) and control (P⬍.001) groups contributing to a significant interlimb asymmetry (see table 2). Arch Phys Med Rehabil Vol 87, May 2006

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HAND FUNCTION AND CORTICAL OUTPUT IN STROKE, Brouwer Table 2: Values Associated With Tests of Hand Function and Responses to Cortical Stimulation by Group and Target Limb Control Tests and Responses

Taps (total) Pegs (total) MVC (AU) Motor threshold (%) MEP amplitude (mV) MEP latency (ms) Silent-period duration (ms)

Right

250.2⫾54.3 43.1⫾7.9 3.3⫾1.1 56.8⫾9.3 2.50⫾1.21 20.2⫾2.1 147.8⫾23.0

Chronic Left

Nonparetic §

225.9⫾52.9 40.4⫾8.1§ 3.3⫾0.8 58.1⫾9.9 2.25⫾1.35 20.1⫾2.0 158.4⫾28.3

206.1⫾64.8 33.9⫾7.4*† 2.8⫾1.4 62.6⫾6.4 2.45⫾1.34 20.6⫾1.4 181.6⫾43.0

Subacute Paretic

Nonparetic †§

80.6⫾64.1* 10.6⫾9.9*†§ 1.4⫾1.3*†§ 76.1⫾11.7*†§ 1.15⫾0.84*†§ 21.4⫾1.9 211.8⫾57.8*†

Paretic †

180.3⫾71.3* 31.0⫾6.0*† 2.6⫾1.0 63.0⫾12.5 1.95⫾1.14 20.9⫾1.5 159.5⫾39.1

45.0⫾61.5*†§ 6.4⫾11.1*†§ 0.90⫾1.1*†§ 85.5⫾13.3*†§ 0.34⫾0.39*†‡§ 25.1⫾2.2*†‡§ 232.1⫾74.7*†§

NOTE. Values are mean ⫾ SD. Legend: Symbols refer to significant differences revealed through post hoc analysis after ANOVA (see text): *different from right side, control group; †different from left side, control group; ‡different from paretic side, chronic group; §interlimb difference within a given group.

Silent periods differed by group (P⬍.001) and were abnormally long on the paretic side in chronic (P⬍.001) and subacute (P⬍.025) groups. Examples showing the silent-period responses and their accompanying MEPs recorded from both sides of a representative subject in each group are presented in figure 1. An effect of side (P⬍.001) was evident because silent-period durations were prolonged on the paretic side, although the variability among those with stroke in particular likely contributed to the absence of a group-side interaction (P⫽.061). Analysis of interlimb silent-period symmetry, however, revealed group differences (P⬍.05); the subacute group showed marked asymmetry compared with control subjects (P⬍ .03). The neurophysiologic findings are presented in table 2. Relationships Between Hand Function and Neurophysiologic Indicators Correlation matrices constructed from pooled data showed that lower motor threshold, larger MEPs, shorter latencies, and short-duration silent period on the left or affected side were related to better performance in tests of hand function (Pⱕ .036). From the stroke data alone, cortical excitability (motor

threshold, MEP amplitude) was most strongly linked to tapping ability and FDI strength, although not to the same degree for subjects having chronic and subacute strokes. In the chronic stroke group, subjects with lower thresholds were better at tapping (r⫽⫺.587) and force generation (r⫽⫺.537). In subacute stroke, MEP asymmetry was the best indicator of hand function, accounting for about 28% of the variance in tapping and peg placing and 59% of the variance in strength (ie, greater interhemispheric symmetry was associated with better hand function). Of note was that MAS scores failed to correlate with any TMS outcome measure (all absolute r values ⬍.251) likely because of its nonspecificity to hand function. Scatterplots showing examples of these relationships are shown in figure 2. A summary of correlation coefficients is in table 3. Changes in the Subacute Group Over Time Clinically, impairment was reduced and function improved over time as indicated by increases of 5 to 45 points (mean, 17.4; P⬍.001) in MAS scores. Tapping ability and strength improved over the duration of inpatient rehabilitation as indicated by significant interactions between time and side (Pⱕ

Fig 1. Representative electromyograms from (A) a control subject, (B) a subject with chronic stroke, and (C) a subject with subacute stroke showing side-to-side differences in silent-period duration (vertical dashed lines) and active MEP amplitudes. Note different scaling. Abbreviations: L, left; NP, nonparetic; P, paretic; R, right.

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Fig 2. Scatterplots showing the relations between tapping ability and neurophysiologic measures of (A) motor threshold, (B) MEP amplitude, (C) MEP latency, and (D) silent period duration. The linear regression line and 95% confidence bands based on all data are shown.

paretic side were accompanied by a reduction in motor threshold (P⬍.02) and shortening of the MEP latency, although not to a significant degree (P⫽.095); data are summarized in figure 3.

.017), reflecting that gains were limited to the paretic hand (P⬍.03). This served to reduce the magnitude of interlimb asymmetry evident at discharge. Changes in function on the

Table 3: Correlation Coefficients Corresponding to the Associations Between Measures of Hand Function and Neurophysiologic Indicators Taps* Measures

MT* MT asymmetry MEP amplitude* MEP asymmetry Latency* Latency asymmetry Silent-period duration* SP asymmetry

Pegs*

MVC*

All

Stroke

Chronic

SA

All

Stroke

Chronic

SA

All

Stroke

Chronic

SA

ⴚ.740 ⴚ.605 .696 .613 ⴚ.541 ⴚ.505 ⴚ.374 ⴚ.476

ⴚ.574 ⫺.360 .405 .390 ⫺.202 ⫺.268 ⫺.115 ⫺.331

ⴚ.587 ⫺.418 .220 .164 ⫺.002 ⫺.012 ⫺.074 ⫺.222

ⴚ.503 ⫺.210 .587 .536 ⫺.007 ⴚ.161 ⫺.187 ⫺.317

ⴚ.668 ⴚ.619 .701 .569 ⴚ.582 ⴚ.522 ⴚ.528 ⴚ.411

⫺.266 ⫺.311 .380 .451 ⫺.216 ⫺.232 ⫺.263 ⫺.313

⫺.250 ⫺.052 .382 .298 ⫺.465 ⫺.341 ⫺.016 ⫺.294

⫺.207 ⫺.425 .314 .537 ⫺.159 ⫺.037 ⫺.394 ⫺.261

ⴚ.580 ⴚ.647 .564 .638 ⴚ.420 ⴚ.399 ⫺.497 ⴚ.367

ⴚ.511 ⫺.362 .391 .555 ⫺.089 ⫺.323 ⫺.323 ⫺.337

ⴚ.537 ⫺.314 .255 .350 ⫺.257 ⫺.423 ⫺.208 ⫺.091

⫺.145 ⫺.449 .475 .761 ⫺.530 ⫺.364 ⫺.388 ⫺.308

NOTE. Boldface values are significant at P⬍.05. Asymmetry ⫽ paretic (left) ⫺ nonparetic (right)/(paretic (left) ⫹ nonparetic (right). Abbreviations: All, subjects from all 3 groups; Chronic, chronic group only; MT, motor threshold; SA, subacute group only; Stroke, all stroke subjects. *Data from the paretic or left sides only.

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Fig 3. Mean values ⴙ1 SD obtained for (A) hand-function tests and (B) neurophysiologic measures in subacute stroke assessed on admission to and discharge from inpatient rehabilitation. Abbreviation: SP, silent period.

DISCUSSION The present study showed diminished fine-motor skill and hand function bilaterally after hemispheric stroke, which was accompanied by abnormalities in cortical excitatory and inhibitory systems. Marked interhemispheric asymmetries in MEP and silent-period characteristics distinguished subjects with subacute strokes from those with chronic strokes. Although asymmetry was also evident in chronic stroke, it was less dramatic, suggesting a shift toward normalization (symmetry) with progressive stages of recovery. Observations from subjects over their inpatient rehabilitation period were consistent with this view. In conjunction with these findings, unique neurophysiologic correlates of hand function were identified for each stroke group providing insight into the mechanisms associated with recovery. Higher motor thresholds5,7,8,29 and smaller amplitude MEPS2,6,8,12,15,29 have been associated with the damaged hemisphere secondary to loss of corticomotoneurons, altered membrane excitability in remaining cells, or dispersion of excitatory volleys onto motoneurons.15 The normal side-to-side consistency of motor threshold and MEP characteristics provides a Arch Phys Med Rehabil Vol 87, May 2006

reference point to gauge deficiencies in stroke, whereas corresponding features from the nonlesioned side enable interpretation relating to the underlying cause. For example, motor thresholds on the intact side of 3 subacute subjects in whom MEPs were absent were in the upper range of normal such that further increases because of stroke would likely exceed the maximum stimulator output, rendering cortical neurons inaccessible.7 Paired with the observed reductions in motor threshold over the course of inpatient rehabilitation, the elevated motor threshold in subacute stroke is partly attributed to altered cell-membrane excitability. Such limitations in activating excitable elements by TMS is compatible with smaller MEPs, although given the prolonged latency suggesting compromised conduction, temporal dispersion of neural volleys may also contribute.18 The significant changes in corticospinal excitability that we and others have shown within the first 2 to 4 months poststroke2,6,8 contribute to high measurement variability that may factor into the low sensitivity of these measures in predicting recovery.30 Furthermore, fluctuations in excitability make it difficult to estimate losses in corticospinal connectivity. In chronic stroke, cortical excitability was abnormally low on the affected side, although not to the same extent as in subacute stroke. A progressive shift toward symmetry in excitatory responses is an indicator of recovery5,6 often attributed to the resolution of diaschisis, the biochemical and metabolic changes in structures remote to the lesion that influence the regulation of excitability.6,31 Diaschisis generally resolves within 4 months after ischemic insult because of infarct or secondary to hemorrhagic stroke31 and could account for greater interhemispheric symmetry or less asymmetry in chronic compared with subacute stroke. Alternatively (or additionally), use-dependent cortical reorganization can promote hemispheric equalization of MEP characteristics in stroke.27,32 Compared with subjects in the subacute stage, chronic stroke survivors had less impairment and 35% to 44% better manual dexterity and strength, thus increasing the likelihood that they would actively use their paretic limb in day-to-day activities. Our cross-sectional data preclude definitive conclusions, although the parallel between better function and greater corticospinal responsiveness to TMS is clear. Linear relationships were found between all neurophysiologic measures and hand function, particularly for outcomes reflecting cortical excitability. Intuitively, this is not surprising because it is net excitation that results in motor cortical outflow, a requisite for volitional motor unit recruitment. The robustness of the associations between cortical excitability and manual performance was confirmed by its presence in stroke. Heterogeneity among stroke survivors in terms of time postlesion and clinical severity has been considered a deterrent to finding consistent patterns of association between TMS and function.10,12,30 Indeed, classifying stroke survivors by their recovery stage strengthened the associations and revealed unique correlates. In subacute stroke, the size of the MEP elicited from the lesioned hemisphere relative to the intact side was most strongly linked to hand function, whereas in chronic stroke motor threshold emerged as a correlate of motor behavior. We suggest that fluctuations in excitatory and inhibitory influences within the motor cortex and from areas projecting to it during the subacute stage24,33 result in abnormally high variations in motor threshold such that it is a less reliable indicator of function than in chronic stroke when motor threshold measurements are more stable.34 In contrast, suprathreshold stimulation increases the probability of bringing neurons to threshold even in the presence of fluctuating levels of cortical synaptic activity,19 resulting in comparatively stable MEPs, which are more tightly coupled to hand function. This is

HAND FUNCTION AND CORTICAL OUTPUT IN STROKE, Brouwer

especially so for FDI strength, which must achieve some minimum level before more challenging manual tasks can be accomplished3 and therefore may be a more useful indicator when functional ability is low. Early poststroke excitability changes have been detected in the undamaged hemisphere, which may be because of altered transcallosal influences from the lesion side, the net effect being significant side-to-side asymmetry in MEP amplitudes.35 The functional relevance of this has not been well described, although our findings indicate that greater asymmetry is linked with poorer function. Over time, output from the undamaged hemisphere normalizes,35 which may reduce the sensitivity of MEP asymmetry as an indicator of function. In chronic stroke, compensatory strategies and pathways other than the fast corticospinal tract may contribute to manual performance, thus confounding the relation.3,36 Our findings suggest that associations between cortical excitability and function evolve over time in conjunction with the stage of recovery. Longitudinal studies are required to explore the nature of these relations in detail. Unlike the net facilitation reflected by MEPs, the silent period indicates excitability of cortical inhibitory circuits mediated through the GABABergic system.1,19 Prolonged silentperiod duration in chronic and subacute stroke on the affected side is consistent with earlier reports,37 although its relationship to function has not previously been well described. In general, reduced inhibitory influence is important to establishing a permissive environment for reorganization and redefinition of cortical boundaries.38 Indeed, progressive declines in silent-period duration have accompanied clinical improvements1,6 and our subjects with subacute stroke displayed a similar trend. It follows that shorter silent-period durations would be expected in higher-functioning chronic stroke, although this did not occur to any significant degree. One explanation is that silent-period duration is highly variable across subjects, although consistent within subjects.29,37 Because the silent period associated with the nonaffected hemisphere was abnormally high in chronic stroke, the duration on the lesioned side would reflect this (symmetry being the norm) in addition to any stroke-related alteration. In fact, adopting an asymmetry index of silent-period duration, which effectively diminishes intersubject variability in control subjects,29 showed a shift toward greater symmetry from subacute to chronic stages of recovery and may be a more sensitive indicator of function. Correlation coefficients reflected that associations between hand function and silent-period asymmetry were higher than those related to silent-period duration, although arguably the associations were weak. Prolonged silent-period duration reflects the release of GABABergic neurons, thereby extending the inhibition of active corticomotoneurons or limiting phasic activity.1,37 It is conceivable then that abnormally prolonged silent periods may not necessarily limit function to any appreciable degree when performance is poor and cycles of muscle activation and deactivation are slow as was the case in our subjects with stroke. Notably, the relation between silent-period duration and hand function, particularly peg placing, was significant when data from control subjects were included. CONCLUSIONS TMS revealed significant abnormalities after stroke, although less severe in the chronic stage of recovery than the subacute stage. Our longitudinal data from subjects with subacute stroke confirm that abnormalities in cortical excitability lessen over time, although the rate of change is not uniform for all TMS outcomes. This may explain the emergence of unique

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indicators of cortical excitability identified as correlates of hand function at different stages of recovery, which may relate to the underlying mechanisms of neuromuscular recovery. Acknowledgments: We extend our gratitude to the Departments of Physical Medicine & Rehabilitation and Physical Therapy, St. Mary’s of the Lake Hospital, for providing space and assisting with recruitment, and we thank Margaret Henderson for assistance with data processing. References 1. Classen J, Schnitzler A, Binkofski F, et al. The motor syndrome associated with exaggerated inhibition within the primary motor cortex of patients with hemiparetic stroke. Brain 1997;120: 605-19. 2. Heald A, Bates D, Cartlidge NE, French JM, Miller S. Longitudinal study of central motor conduction time following stroke. 1. Natural history of central motor conduction. Brain 1993;116: 1355-70. 3. Thickbroom GW, Byrnes ML, Archer SA, Mastaglia FL. Motor outcome after subcortical stroke: MEPs correlate with hand strength but not dexterity. Clin Neurophysiol 2002;113:2025-9. 4. Thickbroom GW, Byrnes ML, Archer SA, Mastaglia FL. Motor outcome after subcortical stroke correlates with the degree of cortical reorganization. Clin Neurophysiol 2004;115:2144-50. 5. Traversa R, Cicinelli P, Pasqualetti P, Filippi M, Rossini PM. Follow-up of interhemispheric differences of motor evoked potentials from the ‘affected’ and ‘unaffected’ hemispheres in human stroke. Brain Res 1998;803:1-8. 6. Traversa R, Cicinelli P, Olivieri M, et al. Neurophysiological follow-up of motor cortical output in stroke patients. Clin Neurophysiol 2000;111:1695-703. 7. Trompetto C, Assini A, Buccolieri A, Marchese R, Abbruzzese G. Motor recovery following stroke: a transcranial magnetic stimulation study. Clin Neurophysiol 2000;111:1860-7. 8. Turton A, Wroe S, Trepte N, Fraser C, Lemon RN. Contralateral and ipsilateral EMG responses to transcranial magnetic stimulation during recovery of arm and hand function after stroke. Electroencephalogr Clin Neurophysiol 1996;101:316-28. 9. Arac N, Sagduyu A, Binai S, Ertekin C. Prognostic value of transcranial magnetic stimulation in acute stroke [published erratum in: Stroke 1995;26:336]. Stroke 1994;25:2183-6. 10. Hendricks HT, Pasman JW, van Limbeek J, Zwarts MJ. Motor evoked potentials in predicting recovery from upper extremity paralysis after acute stroke. Cerebrovasc Dis 2003;16:265-71. 11. Pennisi G, Rapisarda G, Bella R, Calabrese V, de Noordhout AM, Delwaide PJ. Absence of response to early transcranial magnetic stimulation in ischemic stroke patients: prognostic value for hand motor recovery. Stroke 1999;30:2666-70. 12. Rapisarda G, Bastings E, Maertens de Noordhout A, Pennisi G, Delwaide PJ. Can motor recovery in stroke patients be predicted by early transcranial magnetic stimulation? Stroke 1996;27:2191-6. 13. Vang C, Dunbabin D, Kilpatrick D. Correlation between functional and electrophysiological recovery in acute ischemic stroke. Stroke 1999;30:2126-30. 14. Escudero JV, Sancho J, Bautista S, Escudero M, Lopez-Trigo J. Prognostic value of motor evoked potentials obtained by transcranial magnetic brain stimulation in motor function recovery in patients with acute ischemic stroke. Stroke 1998;29:1854-9. 15. Catano A, Houa M, Caroyer JM, Ducarne H, Noel P. Magnetic transcranial stimulation in acute stroke: early excitation threshold and functional prognosis. Electroencephalogr Clin Neurophysiol 1996;101:233-9. 16. Manganotti P, Patuzzo S, Cortese F, Palermo A, Smania N, Fiaschi A. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin Neurophsyiol 2002;113:936-43. Arch Phys Med Rehabil Vol 87, May 2006

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