Cerebral Lateralization of Language in Normal Left-handed People Studied by Functional MRI

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[Articles]

Neurology

Nmero: Volume 52(5), 23 March 1999, pp 1038-1043

Copyright: 1999 American Academy of Neurology

Tipo de publicacin: [Articles]

ISSN: 0028-3878

Registro: 00006114-199903230-00027

Cerebral lateralization of language in normal left-handed people studied by functional MRI

Pujol, Jess MD; Deus, Joan PhD; Losilla, Josep M. PhD; Capdevila, Antoni MD

Informacin sobre el autorFrom the Magnetic Resonance Center of Pedralbes (Drs. Pujol, Deus, and Capdevila), Barcelona; and the Department of Psychobiology and Methodology (Dr. Losilla),

Autonomous University of Barcelona, Spain.

Received September 11, 1998. Accepted in final December 12, 1998.

Address correspondence and reprint requests to Dr. Jess Pujol Magnetic Resonance Center of Pedralbes, Monestir, 3, 08034 Barcelona, Spain.

Article abstract

Objective: To use functional MRI (fMRI) to further define the occurrence of left-hemisphere, bilateral, and

right-hemisphere language in a normal left-handed population.

Methods: A total of 100 healthy volunteers, consisting of 50 left-handed subjects and a reference group of 50

right-handed subjects, were studied by fMRI of the frontal cortex during silent word generation.

Results: Ninety-six percent of right-handed subjects showed fMRI changes lateralized to the left hemisphere,

whereas 4% showed a bilateral activation pattern. In contrast, left-hemisphere lateralization occurred in 76% of

left-handers, bilateral activation in 14%, and right-hemisphere lateralization in the remaining 10%. The

predominance of right-hemisphere activation, however, was weak in these cases; only a single left-handed subject

(2%) showed complete right-hemisphere lateralization.

Conclusions: Silent word generation lateralizes to the left cerebral hemisphere in both handedness groups,

but right-hemisphere participation is frequent in normal left-handed subjects. Exclusive right-hemisphere

activation rarely occurred in the frontal lobe region studied.

Cerebral lateralization of language is not as well defined for left-handed people as it is for their right-handed

counterparts.1 The intracarotid amobarbital (Wada) test had contributed to establishing the occurrence of left-

hemisphere, bilateral, and right-hemisphere language in left-handers.2-6 However, this procedure has been

restricted to specific patients owing to its invasiveness. These patients showed a higher probability of abnormal

language organization due to early brain injuries and frequent abnormal cerebral development.6 Therefore,

results from the Wada studies are only partially representative of the normal left-handed population.

Functional MRI (fMRI) provides the opportunity to further assess the cerebral organization of language in

normal individuals noninvasively. Studies already conducted in right-handed subjects suggest that fMRI can

accurately estimate language lateralization if adequate strategies are adopted.7-15 Nevertheless, fMRI

observations in the normal left-handed population are still preliminary.9,13,14

Intrinsic verbal production has proved to be more efficient to lateralize language than receptive language

tasks.7 Lateralized changes occur in different regions of the frontal lobe, showing anatomic patterns that depend

on the specific word generation task used. The bulk of frontal activations, however, regularly occur in the cortex

that surrounds the inferior frontal sulcus, including classical Broca's area, dorsolateral prefrontal cortex

(Brodmann's areas 46 and 9), and premotor cortex.7,8,12

We examined 100 healthy volunteers with fMRI performed at this level of the frontal lobe to evaluate the

relative participation of both hemispheres in silent word generation in 50 left-handed subjects compared with 50

right-handed reference subjects.

Methods. Subjects. A total of 100 university students were recruited to make up homogeneous groups of 50

right-handed and 50 left-handed subjects, each of which included 25 women and 25 men. A personal history was

recorded in each volunteer to exclude neurologic, psychiatric, and relevant medical diseases. Particular care was

taken to rule out subjects with possible brain injuries suffered during the perinatal age and early childhood.

Fourteen additional subjects of both genders and handedness were also screened and examined with fMRI to

procure a reserve group to replace subjects showing eventual poor compliance during imaging assessment.

Group assignation was carried out based on subjects' self-reported handedness, and quantitative assessment

was determined by the 10-item Edinburgh Inventory.16 Scoring was carried out based on Bryden's procedure,17 in

which a particular score may range from 10 (extremely right-handed) to 50 (extremely left-handed). All subjects

reporting right-hand preference produced a score between 10 and 20 points. As expected from previous



reports,1 scoring of subjects considering themselves left-handed showed a wider range. The handedness scores

in this group ranged from 29 to 50 points.

All subjects gave written informed consent before inclusion in this study, which was approved by the local

Investigation Review Board. Mean age of the final whole series was 24.6 4.8 years (24.4 4.0 years for dextrals

and 24.9 5.6 years for sinistrals). Mean age for women was 24.6 4.2 years and for men 24.6 5.5 years. Two

subject were rejected due to psychoactive substance use, and another subject owing to the finding of

intracerebral arteriovenous malformation in the routine MRI performed before each fMRI assessment.

Task and testing procedure. The word generation task used in the activation protocol was standard phonetic

verbal fluency based on the Controlled Word Association Test.18 In this test, the subject is required to generate

words beginning with a designed letter. Eight different letters (F, A, S, C, D, M, P, and R) were used in balanced

random order. Each subject performed the task using his or her native language (Catalan or Spanish). When tested

outside the scanner, subjects produced a mean of 49.1 14.0 words during consecutive 1-minute testing with the

letters F, A, and S. Subjects were required to articulate each evoked word "silently and in its entirety," with only

slight tongue movements. Eyes were closed during scanning time, and motion was minimized by using soft head

and neck holders.

Trials consisted of four 1-minute periods in which rest and activation were alternated. In the first period

subjects were instructed to do nothing. After 1 minute, the specific letter required for the first activation was

given through the system intercom. Attempts to generate words beginning with this letter were performed by

subjects until the order was given to stop the task. Subsequently, another 1-minute rest period was required

until a different second-activation letter was provided. Thus, a functional sequence involved a two-letter trial.

Four functional sequences were obtained in each subject.

Functional MRI. A 1.5-Tesla Signa system (GE Medical Systems, Milwaukee, WI) with standard quadrature head

coil was used. The functional sequence consisted of a spoiled gradient recalled acquisition in a steady state

(GRASS) (repetition time/echo time/pulse angle = 73/60/30) with a 256 64 pixel matrix, within a field of view of 24

cm, and with a section thickness of 4 mm. First-order flow compensation gradients were used. Field homogeneity

was adjusted in each subject at the level of each functional slice by automated shimming on the three axes. Each

image in this protocol lasted 5 seconds. The functional time series consisted of 48 consecutive images obtained in

4 minutes.

fMRI assessment in this study was limited to the part of the lateral frontal lobe in which large changes are

detectable with fMRI during the word generation task used.11-15,19 This region extends around the inferior

frontal sulcus and is anterior to the precentral sulcus, as illustrated in figure 1. Three-dimensional sequences

additionally obtained in the subjects and surface rendering models of the brain were helpful to assist

identification of anatomic landmarks. Well-established anatomic criteria were also used to locate the central,

precentral, and inferior frontal sulci.20,21



Figure 1. The red rectangle on the brain surface rendering delimits the frontal region considered in this study.

Note that this region is above Broca's speech area and is anterior to the precentral sulcus. The slices selected

around the inferior frontal sulcus are represented in green.

Two oblique-axial slices were selected to cover the region of interest, and two functional sequences were

acquired at each location during four separate imaging runs. The inferior frontal sulcus was used as reference for

slice selection. This reference was randomly obtained from either the right of left frontal sulcus to minimize a

possible anatomic bias caused by subject position asymmetries.

Image analysis. Functional sequences were analyzed using an auxiliary workstation (SPARCstation 20; Sun

Microsystems, Mountain View, CA) and specific image analysis software (FuncTool, GE Medical Systems, Buc,

France). Images were reconstructed in 1 256 256 pixel matrix, and t-test images were obtained using procedures

previously described.22,23 One activation image was reconstructed in each functional sequence with the pixel-

by-pixel calculation of t statistics resulting from the comparison of signal intensity obtained during rest and

activation. The pooled variance estimate method of Student's t-test was used in this procedure. The first image of

each trials was excluded from the analysis owing to its precarious steady-state condition. To guide measurements

and to display activations, each t-test image was fused to a corresponding anatomic image. The presence of

motion was finely detected by a researcher blinded to the subjects' data using a cine display method. Sequences

in which detectable motion occurred were not further considered.

Hemispheric lateralization was determined by comparing the number of activated pixels for left and right

hemisphere in the defined prefrontal region. An activation laterality index was computed for each functional

sequence according to the expression 100* (L - R)/(L + R), where L was the number of pixels above the threshold

in the defined frontal region of the left hemisphere and R the corresponding counting for the right hemisphere.

An index of +100 expresses complete lateralization to the left hemisphere whereas an index of -100 represents an

activation entirely lateralized to the right hemisphere. Activation changes surrounding the central sulcus were

additionally analyzed as representative of primary sensorimotor cortex activation.

The four laterality indexes corresponding to the four activation sequences were averaged to provide a single

score in each subject. When functional sequences were not suitable for analysis as a result of head movement or

insufficient activation, the overall laterality index was computed from the average of the remaining sequences.

Subjects showing three or four failing sequences were excluded from the study and replaced by reserve

individuals.

All measurements were performed by a single researcher blind to the handedness and gender of subjects.

Pixel-counting was repeated in 100 activation sequences in two separate sessions to evaluate the reproducibility

of the measurements. We found and intraclass correlation coefficient. of 0.98 for the 100 doubly computed

laterality indexes.



Activation threshold. We used a cluster size threshold in combination with a t value threshold. On the

composite functional images, we displayed those clusters larger than 13 pixels with t values greater than 1.9 (p

Cerebral Lateralization of Language in Normal Left-handed People Studied by Functional MRI

Documents

left hemisphere

left cerebral hemisphere

hemisphere activation

normal lefthanded subjects

andrighthemisphere language

normal lefthanded population

hemisphere participation

lefthanded people