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Parceling of Mesial Frontal Motor Areas During Ideation and Movement Using Functional Magnetic Resonance Imaging at 1.5 Tesla

J. M. Tystka, PhD," S. T . Grafton MD,*+ W. Chew, PhD,*+ R. P. Woods, MD,4 and P. M. Colletti, MD'

Finger movement-related responses were identified in three discrete sites of mesial frontal cortex in 7 normal subjects using high resolution functional magnetic reso- nance imaging. During imagination of the same move- ments there was a differential response with rostral areas more active than caudal areas. Humans have multiple motor areas in mesial frontal cortex that subserve differ- ent functions in motor planning and execution.

Tyszka JM, Grafton ST, Chew W, Woods RP, Colletti PM. Parceling of mesial frontal motor areas

during ideation and movement using functiond magnetic resonance imaging at 1.5 tesla.

Ann Neurol 1994;35:746-749

The implementation of functional magnetic resonance imaging (fMRI) based on blood oxygenation level- dependent (BOLD) contrast using unmodified clinical imagers provides a new method fpr localizing sensory and motor-related activity [l-51. We present the re- sults of a high-resolution BOLD study that details the differences between real and imagined motor tasks in human mesial frontal motor areas. The experiment was motivated by previous studies using radioactive tracers that reveal increased regional cerebral blood flow (rCBF) in the region of the supplementary motor area (SMA) and adjacent cingulate cortex during real or imagined movements {G-83. The relatively low resolu- tion of these studies has prevented a detailed analysis of the number and location of rCBF responses in me- sial cortex. We hypothesized that multiple motor rep- resentations were present in mesial frontal motor areas and that they responded in distinct patterns to real and

From che Depanments of tNeurology and *Radiology, University of Southern California, and $Division of Brain Mapping, Depart- ment of Neurology, University of California at L o s Angeles, Los Angeles, CA. Received Dec 6, 1993, and in revised form Jan 28, 1994. Accepted for publication Feb 16, 1994.

Address correspondence to Dr Tyszka, Cedars-Sinai Imaging Medi- cal Group, 8700 Beverly Blvd, Los Angeles, CA 90048.

746 Copyright 0 1994 by the American Neurological Association

imagined movements [91, noting that previous studies of motor task ideation with BOLD contrast fMRI have concentrated on primary motor, premotor supplemen- tary motor, and somatosensory cortical activation changes {lo, 111.

Materiais and Methods Images were acquired using a General Electric 1.5-tesla (T) Signa Advantage 5x imager with 1.0 Gicm actively shielded gradients and a quadrature head coil. Low resolution radiofre- quency spoiled gradient echo images (SPGR 70/60/10 de- grees 1.4 X 2.8 X 10.0-mm voxels, 1 signal average), which have a high sensitivity to the inhomogeneity weighted trans- verse relaxation time (T,*), were acquired in a sagittal plane centered 5 mm to the left of the midline. For each task, a series of 5 resting and 5 active images was repeated 5 times to generate a total of 50 images in about 10 minutes.

Real and imagined tasks were performed by 8 healthy, right-handed volunteers (mean age ? SD, 30 f 10 yr). An opposing sequential finger-to-thumb tapping paradigm for the right hand was used as the real task and the subject was instructed to imagine performing exactly the same motion of the fingers during the ideation task. Real and ideation tasks were performed separateIy to minimize tasking errors by the subject. No subject was visually observed to move their hand during the ideation or resting periods, though ideally, electro- myography, could be used to verify the absence of isometric muscle activity during resting and ideation phases [ 111. The real and ideation task series were separated by a maximum delay of 45 seconds. Head motion was minimized by heavy foam padding within the head coil.

Image analysis was performed off-line on a SPARCStation 2 (Sun Microsystems, CA). All images for a subject were registered to the first image of the real task series using the AIR package developed by Roger Woods (Department of Neurology, University of California at Los Angeles) [12]. Registration minimized gross in-plane misalignment of suc- cessive images and allowed region-of-interest (ROI) calcula- tions for the two paradigms to be compared directly. A sin- gle-factor analysis of variance (ANOVA) test was performed for a null hypothesis that the resting and activation image pixels belong to the same population [13]. The F ratio was

calculated separately for the real and imagined tasks, on a pixel-by-pixel basis for each subject and was used to generate a parametric map of the signal differences. A threshold of 10% of maximum signal intensity in the series was applied to the raw images before calculation of the F ratio, to elimi- nate areas of bone and air. Calculated F maps for each task were overlaid on either the first image of the series or on a high-resolution anatomic MR image (SPGR 35/7/40 degrees 0.7 X 0.9 X 10.0-mrn voxels, 8 averages), to locate active areas in relation to the cerebral anatomy. This operation was performed using the AVS proprietary software package (Ad- vanced Visualization System, Inc, IL). Active areas for the real movement task were located visually, then an ROI was defined around the observed active area on an individual basis. All pixels within this area with an F ratio of less than 5.0 were discounted. This reduced ROI was then used to calculate the mean percent signal change for that subject dur- ing both tasks. The percent signal was used because the abso- lute signal level is not reproducible from one task series to the next. A paired t test was then performed on the relative signal changes, both between locations and tasks, to establish significance levels (Table). The centroid of each active area was located relative to the anterior-posterior commissural line and the displacement scaled and rotated to Talairach coordinates [14].

Results The maximum in-plane rotations and displacements, in both task series were less than 1.25 degrees, 0.85 mm (x) , and 1.40 m m (y) in all but 2 cases. O f these 2 worst cases, 1 was discarded, and 1 retained following registration and confirmation of the absence of signifi- cant out-of-plane movement by visual inspection; the maximum in-plane rotations and displacements for the retained subject were 7.4 degrees, 1.62 mm (x), and 13.0 m m (y).

Regions of significant signal change ( F > lO.O), p < 0.003) were consistently observed in three locations of mesial frontal cortex during real movements (Fig). T h e first was located in the superior premotor area, adja- cent to the superior sagittal sinus, corresponding to a

Comparison of Percent Signal Changes Witbin the Two Regions Identified in the Figure

Mean Percent Signal Change

Motor Task Posterior Region Anterior Region Row Significance

Real task 2.06 2 0.13 1.98 * 0.11 p = 0.32

Imagined task 0.94 t 0.15 1.27 2 0.19 p = 0.086

Column significance p = 0.000026 p = 0.0027

n = 6

n = 6

n = 7 n = 6 -5.0, -18.3 ? 4.1, 50.4 ? 3.4 Talairach coordinates -5.0, -8.9 ? 3.4, 49.7 ? 2.0

(mm)

The activation, as measured by the percentage difference between resting and tasking signal, decreases in both regions during imaginary tasking. The reduction is more pronounced in the posterior area. Significance was determined by a paired, two-tailed t test. The mean location (.t SEM) of both areas using Talairach coordinates compares well with previous positron emission tomography results of movement related activity IS, 141.

Brief Communication: Tyszka et al: Motor Areas in Human Mesial Frontal Cortex 747

‘2

‘1

tor ideation, responses in both sites decreased in mag- nitude; however, there was a differential change. The anterior response was consistently greater than the pos- terior response during motor ideation, in all but 1 sub- ject, in whom the anterior active region was not ob- served (see Table).

~

F ratio images from I subject, with a minimum threshold of F = 10.0 overlaid on a high-resolution magnetic resonance image of the same slice; all large areas of sign&cant activation have been outlined. The activation m p for the real jnger-tapping task (A) shows the two areas consistently seen in all subjects (arrows). Activution of the more posterior response is educed during ideation of the same task (B). The active region in the superior premotor area (A) was also consistently observed in all subjects but was excluded from analysis due to the possibility of motion contamination from the superior sagittal sinus. Other sig- nificantly active regions are observed in this particular study, most notably in the rostra1 frontal lobe and cingulate gyrus (A) and in the inferior occipital cortex and thalamus (Bi. However, these areas were not observed in other subjects and their signij- cance for these tusks is currently unclear.

putative hand area as defined by cortical stimulation in nonhuman primates [ 157. Although this activation area was consistently observed in all but 1 subject during real tasking, it was excluded from analysis in this study due to its proximity to the sagittal sinus. Significant signal changes were observed at several locations along the sinus, within its lumen, including that adjacent to the superior premotor area, in all but 1 subject, and the possibility of artifactual, motion-related activity could not be discounted. The remaining two sites were located in the ventral supplementary motor area or the dorsal bank of the cingulate sulcus. The two sites differed in their anterior-posterior location and were usually separated by a single gyrus (see Table). The stereotaxic coordinates of the posterior site were coin- cident with anterior cingulate responses previously ob- served in positron emission tomographic (PET) scans of manual activities [S, 161. Both these sites were ac- tive during the real motor task, in all but 1 subject, in which the anterior site was not observed. During mo-

Conclusions With improvements in the resolution of functional im- aging we identified a precise anatomic map of motor related areas of mesial frontal cortex. As with nonhu- man primate species, there are multiple motor repre- sentations in human mesial frontal cortex. Three dis- crete responses could be identified during sequential finger movement. All of the sites are located caudal to the anterior commissural line in the supplementary motor area or adjacent cingulate cortex. No responses were seen rostral to the anterior commissure. It has been suggested that responses in the more rostral me- sial cortex are associated with more complex types of movements than the simple finger tapping in our ex- periment Cl6l.

The most interesting result is the differential effect of imagined versus real movement. The more anteri- orly located area responded to a greater degree with ideation than the posterior location, suggesting these sites contribute to the ogranization of movement dif- ferently. One interpretation of this is that the anterior site is more closely coupled with limbic cortex, and may participate in the funneling of thoughts about movement into motor executor areas, and the poste- rior site is more closely related to the execution of motor behavior [ 171.

With conventional gradient echo imaging at 1.5 T the BOLD contrast is concentrated in both larger ves- sels and active tissue. This causes potential problems in interpreting the results, particularly in areas close to large vessels such as the sagittal sinus. As such, the technique used here should be treated as a “functional angiogram” indicating only an approximation of the magnitude and location of parenchymal activity. Nev- ertheless, the location of discrete responses and marked change of activity between tasks in the current study were reproducible across subjects and reveal both anatomic and functional segregation in multiple motor areas of mesial frontal cortex.

This work was supported in part by NINDS grant KS-08 NS01568 (S.G.)

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748 Annals of Neurology Vol 35 No 6 June 1994

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Treatment of Guillain-Bar6 Syndrome with High-Dose Immune Globdns Combined with Methylprednisolone: A Pilot Study The Dutch Guillain-BarrC Study Group

In an open study 25 patients with Guillain-BarrC syn- drome were treated for 5 days with intravenous immune globulins in a dose of 0.4 gmlkg of body weightlday and 0.5 gm of methylprednisolone intravenously per day. The results of this combined treatment were compared with the results from a group of 74 patients who were treated with immune globulins only in a recent Dutch Guillain-Bard trial. In the methylprednisolone- immune globulin treatment group, 19 of 25 patients (76%) improved by one or more functional grades after 4 weeks, as compared with 39 (53%) of 74 patients treated with immune globulin alone ( p = 0.04). Also the median time required to the stage of walking in- dependently was reduced in the methylprednisolone- immune globulin treatment group. This pilot study sug- gests that combined treatment with methylprednisolone and immune globulins in patients with the Guillain- Barre syndrome is more effective than treatment with immune globulins alone; a randomized clinical trial might confirm this.

T h e Dutch Guillain-BarrC Study Group. Treatment of Guillam-Barre syndrome with high-dose immune

globulins combined with methylprednisolone: a pilot study. Ann Neurol 1994;35.749-752

The Study Group consists of the following members: Writing Com- mittee: L. H . Visser, P. I. M. Schmitz (statistician), P. A. van Doorn, and F. G. A. van der MechC; Steertq Committee: F. G. A. van der Meche (Chairman), P. I. M. Schmitz, P. A. van Doorn, J. Meulstee, and A. E. J. de Jager; Coordinator: L. H. Visser; Organization Coordi- nating Center (University Hospital Dij kzigt, Erasmus University, Rotterdam): R. M. van den Hoven; Other Centm: Canisius- Wilhelrnina Ziekenhuis, Nijmegen-M. J. J. Prick, C. W. G. M. Frenken, and W. I. M. Verhagen; St. Clara Ziekenhuis, Rotterdam-H. J. van den Brand and H. A. W. Sinnige; Westeinde Ziekenhuis, Den Haag-W. F. M. Arts, A. W. de Weerd, and F. Leijten; Merwede Ziekenhuis, Dordrecht-R. P. Klcyweg; Medisch Centrum Alkmaar-J. A. van Leusden; Academisch Ziekenhuis Maastricht-J. Verschuren and A. v. d. Heijden-Montfroy; and St. Elisabeth Ziekenhuis, Tilburg-A. A. W. Op de Coul and R. L. A. A. Schellens.

Address correspondence to L. H. Visser, Department of Neurology and Trial Center for Neurological Diseases, University Hospital Dijkzigt and Erasmus University, Rotterdam, Ee2234, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands. Received Sep 24, 1993, and in revised form Dec 13. Accepted for publication Dec 14, 1993.

Copyright 0 1994 by the American Neurological Association 749