Donate Help Contact The AHA Sign In Home
American Heart Association
Stroke
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Stroke. 1997;28:2518-2527

This Article
Right arrow Abstract Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cramer, S. C.
Right arrow Articles by Rosen, B. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cramer, S. C.
Right arrow Articles by Rosen, B. R.
Right arrowPubmed/NCBI databases
Medline Plus Health Information
*MRI Scans

(Stroke. 1997;28:2518-2527.)
© 1997 American Heart Association, Inc.

Articles

A Functional MRI Study of Subjects Recovered From Hemiparetic Stroke

Steven C. Cramer, MD; Gereon Nelles, MD; Randall R. Benson, MD; Jill D. Kaplan, MD; Robert A. Parker, ScD; Ken K. Kwong, PhD; David N. Kennedy, PhD; Seth P. Finklestein, MD; Bruce R. Rosen, MD, PhD

From the Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass (S.C.C., G.N., J.D.K., D.N.K., S.P.F.); The Neurorecovery Program, Massachusetts General Hospital and Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, Mass (S.C.C., G.N., J.D.K., S.A.F.); The Clinical Investigator Training Program, Harvard-MIT Division of Health Sciences and Technology and Beth Israel-Deaconess Medical Center in collaboration with Pfizer Inc. (S.C.C.); The MGH-NMR Center, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass (S.C.C., R.R.B., K.K.K., D.N.K., B.R.R.); Biometrics Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (R.A.P.); The Center for Morphometric Analysis, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass (D.N.K.); and Department of Neurology, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, Mass (G.N., J.D.K.).

Correspondence to Steven C. Cramer, MD, VA Medical Center, Department of Neurology (127), 1660 S Columbian Way, Seattle, WA 98108. E-mail cramers{at}uwashington.edu


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background and Purpose Stroke recovery mechanisms remain incompletely understood, particularly for subjects with cortical stroke, in whom limited data are available. We used functional magnetic resonance imaging to compare brain activations in normal controls and subjects who recovered from hemiparetic stroke.

Methods Functional magnetic resonance imaging was performed in ten stroke subjects with good recovery, five with deep, and five with cortical infarcts. Brain activation was achieved by index finger-tapping. Statistical parametric activation maps were obtained using a t test and a threshold of P<.001. In five bilateral motor regions, the volume of activated brain for each stroke subject was compared with the distribution of activation volumes among nine controls.

Results Control subjects activated several motor regions. During recovered hand finger-tapping, stroke subjects activated the same regions as controls, often in a larger brain volume. In the unaffected hemisphere, sensorimotor cortex activation was increased in six of nine stroke subjects compared with controls. Cerebellar hemisphere contralateral and premotor cortex ipsilateral to this region, as well as supplementary motor areas, also had increased activation. In the stroke hemisphere, activation exceeding controls was uncommon, except that three of five cortical strokes showed peri-infarct activation foci. During unaffected hand finger-tapping, increased activation by stroke subjects compared with controls was uncommon; however, decreased activation was seen in unaffected sensorimotor cortex, suggesting that this region's responsiveness increased to the ipsilateral hand and decreased to contralateral hand movements. Use of a different threshold for defining activation (P<.01) did not change the overall findings ({kappa}=.75).

Conclusions Recovered finger-tapping by stroke subjects activated the same motor regions as controls but to a larger extent, particularly in the unaffected hemisphere. Increased reliance on these motor areas may represent an important component of motor recovery. Functional magnetic resonance imaging studies of subjects who recovered from stroke provide evidence for several processes that may be related to restoration of neurologic function.


Key Words: stroke outcome • magnetic resonance imaging • motor activity


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowSubjects and Methods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Hemiparesis is the most common deficit after stroke, affecting greater than 80% of subjects acutely and greater than 40% chronically.1 There is a wide range in the degree of recovery.2 The restorative processes occurring in the brain after stroke remain incompletely understood.

Studies in animals have provided several insights into the basis for recovery. First, electrophysiological studies in monkeys demonstrated that recovery from an experimentally induced focal lesion in primary sensory3 or motor4 cortex may be associated with peri-infarct reorganization of the hand representational map. Second, increased activation in the supplementary motor area (SMA) has also been identified in association with motor recovery.5 Third, a number of cellular and histological changes have been documented in the unaffected hemisphere during recovery from stroke. For example, rats given a focal cortical lesion develop cortical dendrite expansion in sensorimotor cortex of the unaffected hemisphere, which peaks at day 18 postlesion; interventions reducing this dendritic response are associated with less recovery.6

These three processes have also been found in humans both normally and during stroke recovery. For example, plasticity of the motor cortex representational map has been described with motor learning in normal subjects.7 After unilateral brain insult, rearrangement of motor maps has been identified in the unaffected8 and stroke-affected9 hemisphere using transcranial magnetic stimulation. Recruitment of SMA has been described as a normal accompaniment to anticipation or sequencing of a motor task, as well as performance of a complex task.10 Clinical studies suggest that SMA may contribute to return of motor function after stroke.11 Increased task complexity is associated in normal subjects with increased activity in motor cortex ipsilateral to the active hand.12 13 Weiller et al,14 using positron emission tomography (PET), studied subjects who recovered from deep capsular infarct and found individual patterns of increased cerebral blood flow (CBF) in multiple brain regions, including bilateral sensorimotor cortex and SMAs. Although these studies have provided insight into the cerebral responses to stroke, additional functional neuroimaging studies are needed to further characterize these processes, such as examination of a wider range of stroke subtypes.15

In the current study, functional magnetic resonance imaging (fMRI) was used to determine if increased activation in peri-infarct foci, SMA, or unaffected hemisphere motor regions was present as evidence for operation of the above processes in stroke recovery. fMRI with blood oxygenation level-dependent contrast uses the intrinsic paramagnetic signal of deoxyhemoglobin, rather than exogenous or radioactive tracers, to detect the local changes in blood flow, which occur in association with neuronal activation.16 17 18 Its excellent spatial and temporal resolution makes it ideal for the study of functional brain anatomy. Activation patterns in healthy subjects were compared with those found in subjects who recovered from stroke, including subjects who recovered from a cortical infarct, a group not previously examined with PET or fMRI. We found patterns of motor activation in normal subjects that were similar to those described previously. Most stroke subjects activated the same motor regions, but to a greater extent within unaffected hemisphere motor areas, SMAs, and foci along the rim of a cortical infarct, suggesting a contribution by all three of the above processes. Subjects with different stroke topographies, but equal degrees of motor recovery, showed similar activation patterns.


*    Subjects and Methods
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 *Subjects and Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Subject Selection and Training
Ten stroke patients with a history of nonhemorrhagic, hemiparetic stroke were identified from review of admitting records to Massachusetts General Hospital and Spaulding Rehabilitation Hospital. Entry criteria were as follows: (1) a stroke that reduced strength to <=4+ on the Medical Research Council scale19 in both wrist extensor and hand interossei muscles for at least 48 hours; (2) good motor recovery defined by resolution of upper extremity synkinesis, improvement in wrist extensor and interossei strength by at least one level on the Medical Research Council scale, and final strength at least 4+ in either wrist extensors or interossei; (3) no prior stroke with sensorimotor deficits. All stroke subjects received postinfarct motor rehabilitation therapy. Stroke topography was classified20 as either deep (lenticulostriate or anterior choroidal artery territory) or cortical infarction. Nine elderly controls (4 males) older than 60 years were recruited through local advertisements; each had a normal neurologic examination, no history of a stroke, and no significant active neurological problems. Neurological examinations were conducted within 2 days of MRI scanning in all but one case. Handedness was evaluated using the Edinburgh Inventory.21 The presence of stroke risk factors was examined, including hypertension, diabetes mellitus, hypercholesterolemia, cigarette smoking, coronary artery disease, and atrial fibrillation. Subjects were trained to tap each index finger at the metacarpophalangeal joint before imaging and further practiced inside the MRI scanner.

MRI Image Acquisition
Echo planar images and conventional images were obtained using a high-speed, whole-body scanner (1.5 Tesla General Electric Signa modified by Advanced NMR Systems) and a quadrature head coil. Head movement was minimized with foam rubber pads and a restraining Velcro band across the forehead, and body movement was limited by placement of bilateral proximal arm straps. Each scanning session included the following: (1) high resolution volumetric gradient echo images, 2.8-mm thickness; (2) an automated shim procedure to improve magnetic field homogeneity;22 (3) flow-compensated images in plane with functional images; (4) high-resolution echo planar anatomic images in plane with functional images; (5) in the stroke subjects, a measurement of relative CBF using the flow-sensitive alternating inversion recovery (FAIR) method23 24 25 in a single supra-Sylvian axial slice; (6) blood oxygen level-dependent contrast functional images, consisting of asymmetric spin echo images for T2* signal change, with TR of 2.5 seconds, TE of 70 mseconds, effective field of view of 20 cm2, and in-plane resolution of 3.1 mm2. One functional study examined right index finger-tapping, and a subsequent study examined left index finger-tapping. Index finger-tapping was selected because such fractionated finger movements represent the highest motor recovered state after stroke.26 The whole brain was examined using 20 contiguous horizontal slices of 7-mm thickness; for stroke subject 4, only the cerebrum (12 slices) was imaged because of use of an alternate imaging protocol. One hundred images were obtained per slice over a 4-minute period, during which subjects alternated between 30-second periods of rest and activity. The first two subjects studied (subjects 1 and 2) tapped at 2 Hz ad libitum, whereas a 2-Hz metronome beep was transmitted through plastic headphones (continuously during rest and active periods) in subsequent studies. The cue to begin and to cease movements was a light tap on the knee. Subjects kept eyes closed at all times. All movements were monitored for accurate performance by one of the experimenters standing in the scanner room at the subject's side.

Image Analysis
Image analysis was performed on Sun SPARC workstations. Head motion was detected and corrected using image registration software adapted for fMRI by Jiang et al27 from Woods et al.28 The algorithm automatically removes the top and bottom slices, because even small amounts of movement through the plane can cause voxels to leave/enter the image volume in these slices. To account for this, imaging was performed so the top slice was superior to the brain and, thus, contained no relevant information. Statistical parametric maps were generated voxel-by-voxel using a t test, contrasting images taken during finger-tapping with those taken at rest. Identification of images as tapping or rest was shifted 5 seconds to account for the delay normally seen in the rise of CBF after neuronal activation.29 Statistical maps were mildly smoothed with a Hanning filter to improve the signal-to-noise ratio, halving the effective in-plane resolution. Maps showing significant motion artifact,30 defined as continuous activation of voxels with P<.001 around the rim of one-fourth or more of the brain circumference on any analyzed slice, were excluded from further analysis.

For each subject, the volume of activation was measured in five bilateral motor regions. By applying region of interest (ROI) template methods described previously,31 32 33 each subject's echo planar high-resolution images were used to generate ROIs for cerebellum, basal ganglia, SMA, premotor cortex (PMC), and sensorimotor cortex (SMC). The SMC was further divided into precentral gyrus and postcentral gyrus for secondary analyses. By using an adaptation of methods described previously,34 parcellation of ROIs was guided by reliable sulcal landmarks35 and a multiplanar radiological brain atlas,36 while viewing the high-resolution gradient echo images reformatted in the three cardinal planes simultaneously. Infarcted tissue was excluded from ROIs. Basal ganglia contained caudate head, globus pallidus, and putamen. Cortical ROI definitions are presented in Fig 1Down. ROIs were generated from anatomic scans, without knowledge of brain activation patterns; the number of significantly activated voxels within each was then counted using a threshold of P<.001.



View larger version (77K):
[in this window]
[in a new window]
  		Figure 1. The cortical ROIs are shown in lateral and medial views of the brain. PMC extended from precentral sulcus to a rostral limit halfway between central sulcus and the anterior-most extent of the brain, brain vertex to Sylvian fissure, and lateral brain surface to SMA. SMA extended rostrocaudally as with PMC, from the brain vertex to the cingulate sulcus and from the midline to the white matter underlying the mesial cortex. SMC extended from the precentral to the postcentral gyrus, brain vertex to Sylvian fissure, and lateral brain surface to the depth of the central sulcus.

An ipsilateral index was calculated for each task and group, defined as (C-I)÷(C+I), where C=contralateral SMC activation volume and I=ipsilateral SMC activation volume. The Wilcoxon test was used to compare values for control-right finger tap with stroke subjects-recovered finger tap (recovered finger was the right for all but 2 stroke subjects) and control-left finger tap with stroke subjects-unaffected finger tap.

Values for relative CBF were obtained by subtracting flow-insensitive from flow-sensitive images for 64 pairs of images.23 24 25 The mean value for relative CBF, obtained from the 64 pairs of subtractions, was measured in each voxel of noninfarcted cortex within the territory of the middle cerebral artery.20 These results were then compared with an identically sized, symmetrical set of voxels from the unaffected hemisphere.

Statistics
Within each ROI, increased activation in stroke subjects was identified by comparing the number of activated voxels for each stroke subject against a distribution generated from all control subjects' activations for the same task. To accomplish this, the mean number of activated pixels among control subjects was treated as a Poisson-distributed variable for each of the ROIs, separately for each task. A one-sided upper 95% confidence limit was then calculated. In the majority of cases, a conventional two-sided confidence interval included zero, leading to use of a one-sided limit. Increased activation in a stroke subject was considered to be present in an ROI when the number of activated voxels exceeded the 95% upper limit established in controls for that ROI. Activation data from stroke subjects right finger-tapping were compared with data from control subjects right finger-tapping; left finger-tapping data between the two groups were also compared. Results of these comparisons were then classified as related to paretic or to unaffected finger-tapping. Decreased activation in stroke subjects was identified by comparing activation in controls with a new Poisson distribution generated from stroke subjects. To simplify this comparison, available data from only the eight subjects with left-sided infarcts were used in this analysis. Control right finger-tapping results were then compared with recovered (right) finger-tapping and control left tapping with unaffected (left) finger-tapping, separately for each task and ROI. An ROI with more than four control subjects exceeding the 95% upper limit derived from stroke subjects was considered to be indicative of decreased activation in stroke subjects.

To insure that results were not dependent on the threshold used to define significance, all calculations for recovered finger-tapping were repeated using a threshold of P<.01 rather than P<.001. A {kappa} statistic was then used to assess the degree of agreement between the two different thresholds in identifying increased activation in stroke subject ROIs.

A FAIR study of relative cortical CBF was performed in seven of the stroke subjects; two other subjects were studied before FAIR was added to the protocol, whereas in a third, FAIR was omitted. For the CBF measurements, the distribution of values of relative cortical CBF from the stroke-affected hemisphere was compared with the distribution from the unaffected hemisphere using a Wilcoxon test; significance level was set at P<.05.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 *Results
down arrowDiscussion
 down arrowReferences
 
Clinical and demographic information on the stroke subjects are presented in Table 1Down. The topography of each cortical infarct is described; none abolished the hand area37 on the precentral gyrus. All stroke and control subjects were right-handed. Cerebral arterial anatomy, visible on the flow-compensated images, was normal in all subjects except for an occluded left internal carotid artery in one stroke (subject 10) and in one control subject, each of whom had symmetrical cortical CBF as measured with the FAIR perfusion method. Two stroke subjects had radiologic evidence of prior strokes: Subject 1 had an asymptomatic lacuna in the right putamen discovered at the time of fMRI, and subject 7 had a known infarct of the right occipital pole 6 years prior, which resulted in an isolated left homonymous hemianopsia. Because the imaging field was constrained by placement of the top slice at the dorsum of the brain, variable portions of inferior cerebellum were not imaged because of variations in brain size. The mean number of voxels did not differ between the stroke and the control subjects for any of the ROIs (P>.1 in each case). Mean ROI size ranged from 129 voxels in basal ganglia to 925 voxels in SMC.


View this table:
[in this window]
[in a new window]
  		Table 1. Clinical and Demographic History

Brain Activations (Fig 2Down)
Normal Subjects
One study was excluded because of excess motion (right finger tap). One subject had small amounts of middle finger movement during right finger-tapping, and another had some thumb flexion during left finger-tapping. The principal ROIs activated (mean number of activated voxels, >=4) during right (dominant) index finger-tapping were contralateral SMC (mean of 15.1 voxels activated), ipsilateral cerebellum (9.6), ipsilateral SMA (4.5), and contralateral SMA (4); the mean number of activated voxels was 3.1 for contralateral cerebellum, 1.4 for ipsilateral SMC, and .25 for ipsilateral PMC. During left (nondominant) index finger-tapping, principal ROIs activated (mean number of activated voxels, >=4) were contralateral SMC (29.2), ipsilateral cerebellum (25.2), ipsilateral SMC (9.8), contralateral SMA (8.4), and contralateral cerebellum (8.2); the mean number of activated voxels for ipsilateral cerebellum was 3.8. Basal ganglia activation was inconsistently seen; bilateral activation of basal ganglia during motor task performance is more apparent with higher magnetic fields and alternate imaging strategies.38 In most cases, control subjects had larger ipsilateral and contralateral SMC activations with tapping of the left, nondominant finger compared with the right, dominant finger. The values for SMC activation are presented in Table 2Down. A typical control study is presented in Fig 2Down.



View larger version (125K):
[in this window]
[in a new window]
  		Figure 2. Row 1. fMRI activation images from control subject 2, a healthy 70-year-old. Axial images were taken while the subject alternated between rest and tapping the right index finger. The map of the P values has been color-encoded (see color bar to the right of the images) and superimposed on the high-resolution echo planar anatomic images, which appear in radiologic convention. The P value for each 3x3x7 mm voxel reflects the degree of significance with which local blood flow, an indicator of neuronal activity, varied with finger-tapping. White arrowheads indicate the central sulcus. These images show activation in the left SMC (14 voxels achieving significance), left PMC (6 voxels), left SMA (4 voxels), and right SMC (1 voxel). Row 2. Stroke subject 1, an 86-year-old who recovered from a left deep infarct, which is located ventral to the images shown. Sites with increased activation during tapping of the recovered, right index finger included bilateral SMC and SMA. Note that this subject's 2-Hz tapping was internally generated, without a metronome. Row 3. Stroke subject 3, a 55-year-old studied 11 days after a left deep infarct, which is located ventral to the images shown. Tapping the recovered, right index finger produced left SMC activation, which did not exceed the 95% confidence limit defined by control values. Right SMC activation, however, was increased compared with controls. Row 4. Stroke subject 7, a 66-year-old studied 15 months after a right cortical infarct, which is outlined in yellow in the image at left. Tapping the recovered left index finger produced increased activation in bilateral SMC. Peri-infarct activation is apparent in premotor and in postcentral gyrus foci. Increased activation in the stroke-side SMA and cerebellum are shown in the image to the right. In this sagittal reconstruction, the left side of the figure is anterior. Row 5. Stroke subject 10, a 77-year-old studied 12 months after a left cortical infarct, which has atrophied considerably and is outlined in yellow in the image on the left. Tapping the recovered right index finger produced activation at the hand area along the central sulcus (right image) as well as at a peri-infarct focus two slices (14 mm) ventrally (left image).


View this table:
[in this window]
[in a new window]
  		Table 2. Number of Significantly (P<.001) Activated Voxels in Each SMC During Each Task

Stroke Subjects, Unaffected Hand Index Finger Tap
Subject 10 was excluded because of excess motion, and data were not acquired for subject 2. The principal ROIs activated during unaffected finger tap were the same compared with left finger tap by controls (unaffected finger was on the left in eight of ten stroke subjects), except that SMA activation was ipsilateral to the tapping finger, not contralateral. Unaffected finger-tapping by stroke subjects exceeded control values in very few cases. In five of eight evaluable studies, no ROI exceeded the 95% upper limit defined in controls. Increased activation was seen in unaffected hemisphere SMC and SMA for subject 3, stroke-side cerebellum for subject 7, and stroke-side SMC plus PMC for subject 5. Decreased activation was identified in one ROI, the contralateral SMC, where six control subjects (left finger tap) exceeded the 95% upper limit derived from data on stroke subjects with left-sided infarct (left finger tap).

Stroke Subjects, Recovered Hand Index Finger Tap (Fig 2Up)
Subject 4 was excluded because of excess motion. Mirror movements in the unaffected hand were visible during scanning in only one case, subject 1, in whom they were very small. Subjects 3 and 5 showed very small simultaneous movement of recovered hand thumb, whereas subject 10 had minimal middle finger movement; these movements were present during <25% of index finger taps. The principal ROIs activated during recovered finger tap included all of the regions activated by controls during right finger tap (recovered finger was on the right in eight of ten stroke subjects). In addition, three other regions exceeded a mean of four activated voxels: SMC and PMC ipsilateral to the tapping finger and cerebellum contralateral to the tapping finger. The volume of brain activated during recovered finger-tapping frequently exceeded the 95% upper limit defined in controls, with one or more ROIs showing increased activation in seven of nine studies.

The most common ROI with increased activation was the SMC of the ipsilateral, unaffected hemisphere (Fig 2Up), where six stroke subjects (1, 2, 3, 6, 7, and 10) exceeded the 95% upper limit defined by normals. Use of an ipsilateral index also identified increased ipsilateral SMC activation in stroke subjects (Table 2Up). In contrast, only three subjects (1, 7, and 10) showed increased activation in the contralateral stroke-side SMC. The voxel counts for right and for left SMC are shown for individual subjects in Table 2Up. Some SMC activations were centered anterior to the central sulcus, and some were posterior. This was equally true in control and stroke subjects. Thus, when separate Poisson distributions for precentral and postcentral gyri were created in the unaffected hemisphere, increased activation was found exclusively in the same six subjects who had increased activation when these two gyri were combined as SMC. Likewise, the same three subjects with increased stroke-side SMC activation were those with an increased activation after SMC subdivision.

Three other areas often showed increased activation, but only among subjects with increased activation in unaffected SMC. Five of nine subjects (1, 2, 6, 7, and 10) showed increased activation in either SMA (unaffected side, three cases; stroke-side, four cases; both, two cases; see Fig 2Up). Four subjects (1, 2, 6, and 10) showed increased activation in unaffected hemisphere PMC. Stroke-side cerebellum (ie, the cerebellar hemisphere contralateral to unaffected hemisphere SMC) showed increased activation in five subjects (1, 2, 6, 7, and 10).

An additional pattern of increased activation was found in three (subjects 7, 9, and 10) of the five subjects with cortical stroke. In these three subjects, contralateral SMC activations were present at the hand area along the central sulcus37 ; however, foci of increased activation were also present within one voxel of the infarct rim (Fig 2Up). For subject 7, one was located on the central sulcus, two were on the postcentral sulcus, and one was in premotor areas. For subject 9, one was located on the precentral gyrus, and one was on the postcentral gyrus. For subject 10, two were located on the precentral gyrus, and one was in premotor areas.

Stroke-side PMC showed increased activation in one subject. Unaffected side cerebellum showed increased activation in three subjects, one of whom also showed increased activation in stroke-side SMC. Unaffected hemisphere basal ganglia showed increased activation in two subjects. Stroke-side basal ganglia did not show increased activation in any of the stroke subjects. Recovered finger-tapping was not associated with decreased activation in any ROI.

Values for the ipsilateral index are presented in Table 2Up. Values for recovered finger-tapping (right side in eight of ten subjects) by stroke subjects ranged from -.5 (predominantly ipsilateral activation) to +1 (contralateral activation only), with a mean of +.44. This value is significantly less than that found in controls-right finger-tapping (range, +.56 to +1, mean, +.84; P<.05), indicating a relatively increased reliance on ipsilateral SMC by stroke subjects. A trend toward a lower index for stroke subjects-unaffected finger tap (+.49) compared with controls-left finger tap (+.69) did not achieve significance (P>.5).

Varying the threshold used to define activation in a voxel had little impact on patterns of increased activation in stroke subjects. Control and stroke subjects both showed an increased number of activated voxels when the threshold for significance was changed from P<.001 to P<.01, but little changed on comparing the two groups. Substantial39 agreement between the two thresholds was found ({kappa}=.75) on comparing the stroke subject ROIs identified as having increased activation during recovered finger-tapping.

For subjects with deep stroke (3 and 5), the FAIR slice was located immediately supra-Sylvian and did not include infarct. The FAIR slice was through the infarct, as intended, for cortical stroke subjects 6, 7, 9, and 10; for subject 8, the slice was inferior to the cortical infarct. No significant asymmetry in cortical CBF was present in six of these subjects. In one subject (subject 5), relative CBF in stroke-side cortex was 134% of unaffected side cortex, suggesting either increased flow in the stroke-side hemisphere or decreased flow in the unaffected hemisphere. Although magnetic resonance angiogram was normal in this subject, a mild stenosis of the middle cerebral artery in the unaffected hemisphere was suggested by the observation of increased velocities (40%) in that artery during transcranial Doppler examination. One control subject, incidentally discovered to have an occluded left internal carotid artery during acquisition of flow-compensated images, received a FAIR study that showed no asymmetries.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 *Discussion
down arrowReferences
 
In the current study, fMRI was used to evaluate finger-tapping in subjects with good recovery after paretic stroke. In controls, index finger-tapping produced activation in many brain motor areas and were consistent with prior fMRI studies in normal subjects.13 40 41 In subjects who recovered from a stroke, the same motor areas were activated, often to an increased extent. These results are in good agreement with the prior work of Chollet et al42 and Weiller et al.14 43 Results were extended to subjects who recovered from a cortical stroke, an observation not previously described using PET or fMRI. The findings suggest three processes related to motor recovery: activation of a motor network ipsilateral (unaffected hemisphere) to the tapping-finger much greater than that seen in controls, increased degree of SMA activation, and activation of foci along the rim of a cortical infarct.

In recovered stroke subjects, the region most frequently showing an increased volume of activation over controls was the unaffected hemisphere SMC during recovered finger-tapping. Although most controls showed some activation in ipsilateral SMC, an increased volume of brain was activated in this region in six of nine stroke subjects during recovered finger-tapping. The ipsilateral index mitigates the impact of intersubject differences that may exist in the blood oxygen level-dependent response to neuronal activation because it gauges ipsilateral activation relative to that found contralaterally within a given subject. The mean value in controls (.84) is approximately that found by Kim et al (.9),40 whereas the mean value in stroke subjects was significantly lower (.44), consistent with increased reliance on ipsilateral SMC. Recruitment of ipsilateral, unaffected SMC after brain injury has been identified using single photon emission computed tomography,44 PET,14 42 43 fMRI31 and transcranial magnetic stimulation.8 For some stroke and control subjects, SMC activation was on both sides of the central sulcus; in some, it was centered on the precentral gyrus, whereas for others it was on the postcentral gyrus. This variation was similar between stroke and controls, as dividing the SMC into separate precentral gyrus and postcentral gyrus ROIs did not alter the classification of any stroke subject's activation as being increased or not relative to controls. The observations may reflect the normal rostral-caudal variability in motor activation site45 or result from the contribution to corticospinal tract by both the precentral and the postcentral gyri.46 47

The rarity of mirror movements in the current study may shed light on the significance of increased activation in unaffected hemisphere SMC. In a prior PET study,14 all of the subjects showing increased CBF in unaffected hemisphere SMC during use of the recovered hand were also noted to have simultaneous unintended (mirror) movements in the unaffected hand. As a result, the authors could not determine whether the increased activation of unaffected SMC was merely a reflection of mirror movements in the unaffected hand or if such activation genuinely reflected a restorative role by ipsilateral SMC. The occurrence of mirror movements during scanning in only one subject in the current study supports the view that increased activation in unaffected SMC is not merely a marker for simultaneous movement of the unaffected hand. It is conceivable that minute degrees of mirror movement activity might have been found with sensitive methods such as electromyography. Observed activations in unaffected SMC were relatively large, however, and minute muscle forces would be expected to produce relatively small activations.48 Variance in mirror movement incidence between the two studies might be explained by differences in the stroke subject characteristics or by the nature of the intended task. Indeed, Armatas et al49 showed that the relative degree of mirror movements is increased with use of the pinky compared with the index finger. Pinky movements were part of the activating task used by Weiller et al, but not in the current study.

Other evidence supports a restorative role for unaffected SMC. Divergent methods indicate that a relationship normally exists between SMC and ipsilateral hand motor function. Approximately 15% of the corticospinal tract is known to descend undecussated.50 Moving the ipsilateral hand is associated with increased activity in motor cortex neurons, as measured electrophysiologically,51 with fMRI,40 and with magnetoencephalography.12 Cortical stimulation in monkeys52 and in humans using transcranial magnetic stimulation53 has been associated with motor responses in ipsilateral fingers. The relationship between SMC and ipsilateral hand movements may be intensified after injury. Studies of rats with motor recovery after an experimental lesion have identified an expansion of dendritic arborization in pyramidal cells of unaffected SMC. Blocking this histological reaction was associated with a lesser degree of motor recovery in the affected limb,6 54 suggesting that neural growth in unaffected hemisphere SMC is part of an effective brain response to injury.

The stroke subjects showing increased activation of unaffected SMC also showed increased activation of motor regions known to have rich connections with this area, suggesting recruitment of a larger motor network. Thus, a subset of the six stroke subjects with increased activation in unaffected SMC—and no other stroke subjects—showed increased activation in the cerebellar hemisphere contralateral (five subjects) and the PMC ipsilateral (four subjects) to unaffected hemisphere SMC, as well as either SMA (five subjects). Although most control subjects showed some activation in SMC ipsilateral and cerebellum contralateral to the tapping finger, ipsilateral PMC activation occurred in only two of eight controls. These are part of a distributed motor network.55 The existence of a distributed motor network has been suggested in normal subjects at rest,56 during imagined movement,57 during actual finger-tapping,41 in stroke subjects at rest,58 and in stroke subjects during recovered finger-tapping.42 Increased reliance on multiple nodes in this network has been measured with imposition of a more complex task in normal subjects,10 12 13 as well as in the current study during performance of a simple task by stroke subjects. The analogy between performance of a complex task in normal subjects and a simple task in stroke subjects is highlighted by the self-observations of Brodal,59 that "very great mental effort" was needed to use a paretic muscle. The activation results lend support to the notion that motor recovery after stroke is accompanied by increased activity in an unaffected hemisphere motor network, which is normally present, but less active during performance of a simple task.

Unaffected SMC was also the only region in which decreased activation was frequently seen during unaffected finger-tapping. In rats subjected to a unilateral SMC lesion, immobilization of the unaffected forelimb for the first 15 days prevented dendritic growth and produced severe, lasting deficits in the impaired forelimb.54 Together, these observations suggest that during recovery from an infarct, unaffected limb activity drives neuronal changes in unaffected SMC, which are associated with recovery of the affected limb; but after recovery has reached a plateau, unaffected limb activity produces an attenuated response in unaffected SMC, in association with an increased response to affected limb activity.

A second recovery process suggested by the results is increased reliance on motor areas whose efferent tracts descend in parallel with those originating in SMC.11 60 This anatomic arrangement may underlie the increased activation in SMA and PMC, although activity in these areas might also relate to their connections with SMC. Alternatively, SMA activity increases with increased task complexity10 ; increased SMA activation in stroke subjects may, therefore, be further evidence for perceived increased complexity of finger-tapping for this group. The relative increase in SMA activity by subjects 1 and 2 need to be interpreted with caution, as in these two cases tapping rate was internally generated, which is known to produce larger SMA activation compared with externally guided tasks.10

A third recovery process, based on observations in three of five subjects with cortical stroke, relates to peri-infarct activation of foci; this may reflect cortical map reorganization, reliance on alternative motor representation sites, or both. Reorganization of representational maps within the surviving cortex has been identified during cortical stimulation studies in monkeys after experimental infarct in sensory3 or in motor cortex.4 In two recent studies examining adult monkeys with experimental cortical infarcts, hand motor recovery was accompanied by functional reorganization of viable regions of the motor cortex. When monkeys received motor retraining for several weeks postinfarct, the volume of brain representing hand movement expanded and did so at the expense of proximal arm representation.4 When monkeys spontaneously recovered without rehabilitative intervention, the volume of brain representing hand movements diminished, with expansion of proximal arm representation.61 Some of the observed peri-infarct activations may reflect cortical motor map reorganizations similar to those described in the monkeys. A second explanation for activation in peri-infarct foci is that these may represent recruitment of alternative motor representation sites, as have been described histologically62 63 using transcranial magnetic stimulation53 and using fMRI.64 Peri-infarct activation may represent SMC plasticity, recruitment of alternative motor sites, or a completely different phenomenon. In any case, the observation65 that the volume of surviving peri-infarct penumbra correlates with the degree of neurologic recovery suggests that preservation of this rim of tissue provides an increased substrate for recovery processes after stroke.

No differences were apparent between the subjects with deep and those with cortical strokes, with a nearly identical fraction of either subgroup showing increased activation in each ROI; however, differences between the two groups in the time post-stroke and in the incidence of persistent deficits complicate this comparison. Brion et al,66 using Xe CBF methods in paretic stroke subjects during slow squeezing, found that subjects with a cortical infarct had increased CBF within stroke-side SMC and parietotemporal areas, as well as unaffected side parietal, temporal, and occipital areas. Subjects with deep lesions showed CBF increases only in an unaffected side parietal region. Differences in degree of recovery, activation task, and resolution of the imaging technique may account for the divergent findings. Given that a cortical infarct at sites throughout the hemisphere may produce hemiparesis,67 further studies examining larger numbers of subjects with cortical infarcts are needed to better understand recovery processes relevant to this subgroup.

Results of prior studies using divergent methodologies compare favorably with the current study. Lesion studies in monkeys have highlighted potential motor contributions of the cortex outside of SMC. For example, Aizawa et al5 found increased SMA activity during performance of a learned motor task after removal of the primary motor cortex. A potential role for PMC was suggested by the studies of Bucy and Fulton,52 in which removal of the bilateral motor cortex and unilateral premotor cortex produced moderate motor deficits, but removal of the bilateral motor and premotor cortex produced complete paralysis. Cao et al,31 using fMRI to study subjects with unilateral perinatal brain injury, found that movement of paretic fingers was associated with increased activity in ipsilateral SMC. Sabatini et al,44 using single-photon emission computed tomography to study CBF in a subject with a large hemispheric lesion, found that movement of the recovered hand was associated with substantial activation of the ipsilateral SMC and PMC. Weiller et al,14 in a PET study of eight subjects who recovered from deep capsular infarct, found individual patterns of increased activation. Precise comparison with the current study is made difficult by differences in patient population and activation task, but use of the recovered hand was associated with increased CBF in SMC, PMC, and a midline SMA region in many cases. The PET study identified regions with significant increases in CBF using exogenous C15O2 as a tracer, whereas the current study identified regions with significant increases in activated brain volume as determined by endogenous blood oxygen level-dependent contrast. Despite differing methodologies, there is a high level of agreement between the results of Weiller et al and those of the current study. The similarities were preserved when an alternate threshold was used to define significance in the current study, as there was good agreement in the current findings between the two thresholds ({kappa}=.75).

The most important finding in this study is that the motor task that produced large SMA and unaffected hemisphere motor region activations in stroke subjects was also associated with significant activations in these regions in most controls. This is consistent with the observations of Denny-Brown,68 who suggested on the basis of cortical ablation studies that movement return relies on mechanisms present as components of normal function. Most stroke subjects showed increased activation in unaffected hemisphere motor regions, suggesting reliance on the motor network related to this hemisphere, whereas few examples of increased activation in the stroke hemisphere were found. The difference between hemispheric activations was not likely caused by abnormalities in CBF. The FAIR studies, done to obtain an estimate of perfusion in noninfarcted cortical regions, showed symmetric perfusion in all but one case examined. Nevertheless, the current study represents application of a technique reliant on vasoreactivity in a population that by definition has some cerebrovascular pathology. Future fMRI studies of stroke recovery may, therefore, benefit from a measure of CBF in activated voxels as well as in voxels bordering a cortical infarct. In addition, serial fMRI studies commencing before completion of stroke recovery will shed greater light on the specificity of altered brain activation for neurologic recovery. As improved treatments targeting the stroke recovery period emerge,69 70 71 a more precise understanding of stroke recovery mechanisms may be directive. Functional MRI may be valuable in studying these processes.


*    Selected Abbreviations and Acronyms
 
CBF = cerebral blood flow
FAIR = flow-sensitive alternating inversion recovery
fMRI = functional magnetic resonance imaging
PET = positron emission tomography
PMC = premotor cortex
ROI = region of interest
SMA = supplementary motor area
SMC = sensorimotor cortex
TE = echo time
TR = repetition time


*    Acknowledgments
 
Steven C. Cramer was supported by a grant from the National Stroke Association. We thank Drs Verne S. Caviness, Emilio Bizzi, Karina S. Cramer, and Thomas J. Brady for their thoughtful discussions and valuable comments.

Received June 30, 1997; revision received August 26, 1997; accepted September 30, 1997.


*    References
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowSubjects and Methods
 up arrowResults
 up arrowDiscussion
 *References
 

  1. Gresham GE, Duncan PW, Stason WB, Adams HP, Adelman AM, Alexander DN, Bishop DS, Diller L, Donaldson NE, Granger CV, Holland AL, Kelly-Hayes M, McDowell FH, Myers L, Phipps MA, Roth EJ, Siebens HC, Tarvin GA, Trombly CA. Post-Stroke Rehabilitation. Rockville, MD: U.S. Department of Health and Human Services. Public Health Service, Agency for Health Care Policy and Research; 1995.
  2. Duncan PW, Goldstein LB, Matchar D, Divine GW, Feussner J. Measurement of motor recovery after stroke. Stroke.. 1992;23:1084-1089.[Abstract/Free Full Text]
  3. Jenkins WM, Merzenich MM. Reorganization of neocortical representations after brain injury: a neurophysiological model of the bases of recovery from stroke. Prog Brain Res.. 1987;71:249-266.[Medline] [Order article via Infotrieve]
  4. Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science.. 1996;272:1791-1794.[Abstract]
  5. Aizawa H, Inase M, Mushiake H, Shima K, Tanji J. Reorganization of activity in the supplementary motor area associated with motor learning and functional recovery. Exp Brain Res.. 1991;84:668-671.[Medline] [Order article via Infotrieve]
  6. Jones TA, Schallert T. Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci.. 1994;14:2140-2152.[Abstract]
  7. Karni A, Meyer G, Jezzard P, Adams M, Turner R, Ungerleider LG. Functional MRI evidence for adult motor cortex plasticity during motor skill learning. Nature.. 1996;377:155-158.
  8. Cohen LG, Brasil-Neto JP, Pascual-Leone A, Hallett M. Plasticity of cortical motor output organization following deafferentiation, cerebral lesions, and skill acquisition. In: Devinsky O, Beric A, Dogali M, eds. Electrical and Magnetic Stimulation of the Brain and Spinal Cord. New York: Raven Press, 1993:187-200.
  9. Traversa R, Cicinelli P, Bassi A, Rossini PM, Bernardi G. Mapping of motor cortical reorganization after stroke: a brain stimulation study with focal magnetic pulses. Stroke.. 1997;28:110-117.[Abstract/Free Full Text]
  10. Marsden CD, Deecke L, Freund H-J, Hallet M, Passingham RI, Shibasaki H, Tanji J, Wiesendanger M. The functions of the supplementary motor area. In: Luders H, ed. Supplementary Sensorimotor Area. Philadelphia: Lippincott-Raven; 1996:477-487.
  11. Fries W, Danek A, Scheidtmann K, Hamburger C. Motor recovery following capsular stroke: role of descending pathways from multiple motor areas. Brain.. 1993;116:369-382.[Abstract/Free Full Text]
  12. Salmelin R, Forss N, Knuutila J, Hari R. Bilateral activation of the human somatomotor cortex by distal hand movements. Electroencephalog Clin Neurophysiol.. 1995;95:444-452.[Medline] [Order article via Infotrieve]
  13. Rao SM, Binder JR, Bandettini PA, Hammeke TA, Yetkin FZ, Jesmanowicz A, Lisk LM, Morris GL, Mueller WM, Estkowski LD, Wong EC, Haughton VM, Hyde JS. Functional magnetic resonance imaging of complex human movements. Neurology.. 1993;43:2311-2318.[Abstract/Free Full Text]
  14. Weiller C, Ramsay SC, Wise RJS, Friston KJ, Frackowiak RSJ. Individual patterns of functional reorganization in the human cerebral cortex after capsular infarction. Ann Neurol.. 1993;33:181-189.[Medline] [Order article via Infotrieve]
  15. Dobkin BH. Neurologic Rehabilitation. Philadelphia: FA Davis; 1996.
  16. Bandettini PA, Wong EC, Hinks RS, Tikofsky RS, Hyde JS. Time course EPI of human brain function during task activation. Magn Reson Med.. 1992;25:390-397.[Medline] [Order article via Infotrieve]
  17. Prichard JW, Rosen BR. Functional study of the brain by NMR. J Cereb Blood Flow Metab.. 1994;14:365-372.[Medline] [Order article via Infotrieve]
  18. Turner R, Jezzard P. Magnetic resonance studies of brain functional activation using echo-planar imaging. In: Thatcher R, Hallet M, Zeffiro T, John E, Huerta M, eds. Functional Neuroimaging. New York: Academic Press; 1994:69-78.
  19. The Editorial Committee for the Guarantors of Brain. Aids to the Examination of the Peripheral Nervous System. London: Billiere Tindall, 1986.
  20. Damasio H. A computed tomographic guide to the identification of cerebral vascular territories. Arch Neurol.. 1983;40:138-142.[Abstract]
  21. Oldfield RC. The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia.. 1971;9:97-113.[Medline] [Order article via Infotrieve]
  22. Reese TG, Davis TL, Weisskoff RM. Automated shimming at 1.5T using echo planar image frequency maps. J Magn Reson Imaging.. 1995;5:739-745.[Medline] [Order article via Infotrieve]
  23. Kwong KK, Chesler DA, Weisskoff RM, Rosen BR. Perfusion MR Imaging. Mag Reson Med. 1994:1005. Abstract.
  24. Kwong KK, Chesler DA, Zuo CS, Boxerman JL, Baker JR, Chen YC, Stern CE, Weisskoff RM, Rosen BR. Spin echo (T2, T1) studies for functional MRI. Mag Reson Med. 1993:172. Abstract.
  25. Kim S-G. Quantification of relative cerebral blood flow change by flow-sensitive alternating inversion recovery (FAIR) technique: application to functional mapping. Magn Reson Med.. 1995;34:293-301.[Medline] [Order article via Infotrieve]
  26. Twitchell TE. Restoration of motor function following hemiplegia in man. Brain.. 1951;74:443-480.[Free Full Text]
  27. Jiang A, Kennedy DN, JR Baker, Weisskoff RM, Tootell RBH, Woods RP, Benson RR, Kwong KK, Brady TJ, Rosen BR, Belliveau JW. Motion detection and correction in functional MR imaging. Hum Brain Mapping.. 1995;3:224-235.
  28. Woods RP, Cherry SR, Mazziotta JC. Rapid automated algorithim for reslicing PET images. J Comput Assist Tomogr.. 1992;16:620-633.[Medline] [Order article via Infotrieve]
  29. Cohen MS, Bookheimer SY. Localization of brain function using magnetic resonance imaging. Trends Neurosci.. 1995;17:268-277.
  30. Cohen MS, Kosslyn SM, Breiter HC, DiGirolamo GJ, Thompson WL, Anderson AK, Bookheimer SY, Rosen BR, Belliveau JW. Changes in cortical activity during mental rotation: a mapping study using functional MRI. Brain.. 1996;119:89-100.[Abstract/Free Full Text]
  31. Cao Y, Vikingstad EM, Huttenlocher PR, Towle VL, Levin DN. Functional magnetic resonance studies of the reorganization of the human hand sensorimotor area after unilateral brain injury in the perinatal period. Proc Natl Acad Sci U S A.. 1994;91:9612-9616.[Abstract/Free Full Text]
  32. Kim S-G, Jennings JE, Strupp JP, Andersen P, Ugurbil K. Functional MRI of human motor cortices during overt and imagined finger movements. Int J Imag Syst Technol.. 1995;6:271-279.
  33. Kawashima R, Yamada K, Kinomura S, Yamaguchi T, Matsui H, Yoshioka S, Fukuda H. Regional cerebral blood flow changes of cortical motor areas and prefrontal areas in humans related to ipsilateral and contralateral hand movement. Brain Res.. 1993;623:33-40.[Medline] [Order article via Infotrieve]
  34. Caviness VS, Meyer J, Makris N, Kennedy DN. MRI-based topographic parcellation of human neocortex: an anatomically specified method with estimate of reliability. J Cognitive Neurosci.. 1996;8:566-587.
  35. Ono M, Kubik S, Abernathey CD. Atlas of the Cerebral Sulci. Stuttgart: G. Thieme Verlag; 1990.
  36. Damasio H. Human brain anatomy in computerized images. New York: Oxford University Press; 1995.
  37. Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner A, Winkler P. Localization of the motor hand area to a knob on the precentral gyrus. Brain.. 1997;120:141-157.[Abstract/Free Full Text]
  38. Lehericy S, Van de Moortele P-F, Marsault C, Le Bihan D. Anatomical localization of striatal activation during motor tasks: a 3T fMRI study. Neurology.. 1997;48:A251.
  39. Landis RJ, Koch GG. The measurement of observer agreement for categorical data. Biometrics.. 1977;33:159-174.[Medline] [Order article via Infotrieve]
  40. Kim S-G, Ashe J, Hendrich K, Ellermann JM, Merkle H, Ugurbil K, Georgopoulos AP. Functional magnetic resonance imaging of motor cortex: hemispheric asymmetry and handedness. Science.. 1993;261:615-617.[Abstract/Free Full Text]
  41. Boecker H, Kleinschmidt A, Requardt M, Hanicke W, Merboldt KD, Frahm J. Functional cooperativity of human cortical motor areas during self-paced simple finger movements: a high-resolution fMRI study. Brain.. 1994;117:1231-1239.[Abstract/Free Full Text]
  42. Chollet F, DiPiero V, Wise RJS, Brooks DJ, Dolan RJ, Frackowiak RSJ. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann Neurol.. 1991;29:63-71.[Medline] [Order article via Infotrieve]
  43. Weiller C, Chollet F, Friston KJ, Wise RJ, Frackowiak RS. Functional reorganization of the brain in recovery from striatocapsular infarction in man. Ann Neurol.. 1992;31:463-472.[Medline] [Order article via Infotrieve]
  44. Sabatini U, Toni D, Pantano P, Brughitta G, Padovani A, Bozzao L, Lenzi GL. Motor recovery after early brain damage. Stroke.. 1994;25:514-517.[Abstract]
  45. Nii Y, Uematsu S, Lesser RP, Gordon B. Does the central sulcus divide motor and sensory functions? Cortical mapping of human hand areas as revealed by electrical stimulation through subdural grid electrodes. Neurology.. 1996;46:360-367.[Abstract/Free Full Text]
  46. Evarts EV. Precentral and postcentral cortical activity in association with visually triggered movement. J Neurophysiol.. 1974;37:373-381.[Free Full Text]
  47. Fromm C, Evarts EV. Pyramidal tract neurons in somatosensory cortex: central and peripheral inputs during voluntary movement. Brain Res.. 1982;238:186-191.[Medline] [Order article via Infotrieve]
  48. Dettmers C, Fink GR, Lemon RN, Stephan KM, Passingham RE, Silbersweig D, Holmes A, Ridding MC, Brooks DJ, Frackowiak RSJ. Relation between cerebral activity and force in the motor areas of the human brain. J Neurophysiol.. 1995;74:802-815.[Abstract/Free Full Text]
  49. Armatas CA, Summers JJ, Bradshaw JL. Mirror movements in normal adult subjects. J Clin Exp Neuropsychol.. 1994;16:405-413.[Medline] [Order article via Infotrieve]
  50. Nyberg-Hansen R, Rinvik E. Some comments on the pyramidal tract, with special reference to its individual variations in man. Acta Neurol Scand.. 1963;39:1-30.
  51. Tanji J, Okano K, Sato KC. Neuronal activity in cortical motor areas related to ipsilateral, contralateral, and bilateral digit movements of the monkey. J Neurophysiol.. 1988;60:325-343.[Abstract/Free Full Text]
  52. Bucy PC, Fulton JF. Ipsilateral representation in the motor and premotor cortex of monkeys. Brain.. 1933;56:318-342.[Free Full Text]
  53. Wassermann EM, Pascual-Leone A, Hallett M. Cortical motor representation of the ipsilateral hand and arm. Exp Brain Res.. 1994;100:121-132.[Medline] [Order article via Infotrieve]
  54. Kozlowski DA, James DC, Schallert T. Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci.. 1996;16:4776-4786.[Abstract/Free Full Text]
  55. Passingham R. The Frontal Lobes and Voluntary Action. Oxford: Oxford University Press; 1993.
  56. Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med.. 1995;34:537-541.[Medline] [Order article via Infotrieve]
  57. Crammond DJ. Motor imagery: never in your wildest dream. TINS.. 1997;20:54-57.[Medline] [Order article via Infotrieve]
  58. Azari N, Binkofski F, Pettigrew KD, Freund H-J, Seitz RJ. Enhanced regional cerebral metabolic interactions in thalamic circuitry predicts motor recovery in hemiparetic stroke. Hum Brain Mapping.. 1996;4:240-253.
  59. Brodal A. Self-observation and neuro-anatomical considerations after stroke. Brain.. 1973;96:675-694.[Free Full Text]
  60. Strick PL. Anatomical organization of multiple motor areas in the frontal lobe: implications for recovery of function. In: Waxman S, ed. Functional Recovery in Neurological Disease. New York: Raven Press; 1988.
  61. Nudo RJ, Milliken GW. Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys. J Neurophysiol.. 1996;75:2144-2149.[Abstract/Free Full Text]
  62. Geyer S, Ledberg A, Schleicher A, Kinomura S, Schormann T, Burgel U, Klingberg T, Larsson J, Zilles K, Roland PE. Two different areas within the primary motor cortex of man. Nature.. 1996;382:805-807.[Medline] [Order article via Infotrieve]
  63. He SQ, Dum RP, Strick PL. Topographic organization of corticospinal projections from the frontal lobe: motor areas on the lateral surface of the hemisphere. J Neurosci.. 1993;13:952-980.[Abstract]
  64. Sanes JN, Donoghue JP, Thangaraj V, Edelman RR, Warach S. Shared neural substrates controlling hand movements in human motor cortex. Science.. 1995;268:1775-1777.[Abstract/Free Full Text]
  65. Furlan M, Marchal G, Viader F, Derlon J-M, Baron J-C. Spontaneous neurological recovery after stroke and the fate of the ischemic penumbra. Ann Neurol.. 1996;40:216-226.[Medline] [Order article via Infotrieve]
  66. Brion J-P, Demeurisse G, Capon A. Evidence of cortical reorganization in hemiparetic patients. Stroke.. 1989;20:1079-1084.[Abstract/Free Full Text]
  67. Mohr JP, Foulkes MA, Polis AT, Hier DB, Kase CS, Price TR, Tatemichi TK. Infarct topography and hemiparesis profiles with cerebral convexity infarction: the Stroke Data Bank. J Neurol Neurosurg Psychiatry.. 1993;56:344-351.[Abstract]
  68. Denny-Brown D. Disintegration of motor function resulting from cerebral lesions. J Nerv Ment Dis.. 1950;112:1-45.[Medline] [Order article via Infotrieve]
  69. Clark WM, Warach SJ. Randomized dose response trial of citicholine in acute ischemic stroke. Neurology.. 1996;46:A425.
  70. Kawamata T, Alexis NE, Dietrich WD, Finklestein SP. Intracisternal basic fibroblast growth factor (bFGF) enhances behavioral recovery following focal cerebral infarction in the rat. J Cereb Blood Flow Metab.. 1996;16:542-547.[Medline] [Order article via Infotrieve]
  71. Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R. Amphetamine paired with physical therapy accelerates motor recovery after stroke: further evidence. Stroke.. 1995;26:2254-2259.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Cereb CortexHome page
J. D. Schaechter and K. L. Perdue
Enhanced Cortical Activation in the Contralesional Hemisphere of Chronic Stroke Patients in Response to Motor Skill Challenge
Cereb Cortex, March 1, 2008; 18(3): 638 - 647.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurophysiol.Home page
Y. Murata, N. Higo, T. Oishi, A. Yamashita, K. Matsuda, M. Hayashi, and S. Yamane
Effects of Motor Training on the Recovery of Manual Dexterity After Primary Motor Cortex Lesion in Macaque Monkeys
J Neurophysiol, February 1, 2008; 99(2): 773 - 786.
[Abstract] [Full Text] [PDF]

Home page
 BrainHome page
C. D. Takahashi, L. Der-Yeghiaian, V. Le, R. R. Motiwala, and S. C. Cramer
Robot-based hand motor therapy after stroke
Brain, February 1, 2008; 131(2): 425 - 437.
[Abstract] [Full Text] [PDF]

Home page
 Neurorehabil Neural RepairHome page
D. Lule, V. Diekmann, J. Kassubek, A. Kurt, N. Birbaumer, A. C. Ludolph, and E. Kraft
Cortical Plasticity in Amyotrophic Lateral Sclerosis: Motor Imagery and Function
Neurorehabil Neural Repair, December 1, 2007; 21(6): 518 - 526.
[Abstract] [PDF]