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General activation of cerebral metabolism with speech: a PET study
International Journal of Psychophysiology, 14 (1993) 199-208 0 1993 Elsevier Science Publishers B.V. All rights reserved
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199 0167-8760/93/$06.00
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General activation of cerebral metabolism with speech: a PET study Laszlo B. Tamas b, Takashi
Shibasaki
a, Satoru Horikoshi
a and Chihiro
Ohye a
a Department of Neurological Surgery, Gunma University School of Medicine, Maebashi-shi, Gunma-ken (Japan) and b Department of Neurological Surgery, University of California at Davis, Martinez, CA (USA) (Accepted
Key words: Speech;
28 September
Metabolism;
Emission
1992)
tomography;
Aphasia
We report the pattern of metabolic activation of the brain associated with speech, using I50 positron emission tomography (PET) in normal volunteers, as well as patients with or without language deficit. 15 trials were performed on 13 subjects. Regional oxygen metabolism with the subjects at rest was compared to that during a speech-from-memory task. As expected, there was strong activation of Broca’s area and the medial left temporal lobe, corresponding to the motor speech and memory aspects of the task. In addition, botb cerebellar hemispheres and pre-motor areas, as well as the right frontal operculum, supplementary motor area and right parietal lobe were active. This technique provided insight into the mechanism of aphasia in two subjects, even in one whose traditional language areas were structurally and metabolically intact at rest. We conclude that this practical activation technique may be useful not only in studying the physiology of normal brain, but also in understanding functional responses to
INTRODUCTION The first observations about lateralization and localization of function in the brain were made on the effects of experiments of nature such as head injuries, stroke and epilepsy. This led to the concepts of cerebral dominance and of receptive and expressive speech ‘centers.’ The limitations of these concepts were recognized by Hughlings Jackson, who wrote in 1874 that ‘to locate the damage which destroys speech and to locate speech are two different things’ (Jackson, 1874). Several recent lines of evidence suggest that cortical areas involved with speech may be more variable and widespread than previously thought.
Correspondence to: L.B. Tamas, Department of Neurological Surgery, University of California at Davis, V.A. Medical Center, 150 Muir Road, Martinez, CA 94553, USA.
Studies of patients with left hemispheric lesions using CT (Basso et al., 1985) or PET (Metter et al., 1984) imaging found a significant proportion of patients with speech deficits not explained by traditional language models. Cortical stimulation mapping has likewise revealed a much greater variability and wider distribution of language areas than expected (Ojemann, 1983). Finally, increases in cerebral blood flow with speech have been described not only in Broca’s area, but also in both pre-motor and supplementary motor areas and in the right frontal operculum (Friston et al., 1991; Larsen et al., 1978; Petersen et al., 1988; Roland, 1985). Positron emission tomography with 150 permits the study of regional metabolism and blood flow in the human brain during a variety of tasks. In a landmark study, Petersen et al. (1988) showed regional increases of cerebral blood flow specific for sensory, articulatory and semantic aspects of
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language in normal subjects. Using a similar technique, Frith et al. (1991) identified brain regions specifically involved in ‘intrinsic’ and ‘extrinsic’ word generation. Both groups employed statistical analytic techniques which required averaging regional changes among a group of normal subjects. However, because of the highly individual nature of clinical brain lesions, these techniques are difficult to apply with patients. The purposes of the present study were to simply observe patterns of regional brain activation associated with a speech task, and to determine if they could shed light on mechanisms of speech dysfunction in patients.
METHODS ‘SO-Positron emission tomography We have utilized the 150 continuous-inhalation method of Frackowiak et al. to determine regional cerebral oxygen metabolism (rCMR0,) and blood flow (rCBF), details of which have been described (Frackowiak et al., 1980). The Hitachi PCT H-l system was used, which employs 128 detectors, yielding a transverse resolution of 8 mm and slice thickness of 16 mm. I50 was generated in our facility by the Nippon Steel Works Ultramini Cyclotron. A germanium/gallium source was used for attenuation correction.
Each trial began with a CT scan, producing 7 brain images parallel to the orbitomeatal plane and extending upwards from the pons to the vertex. The subject’s bed was then moved on specially installed rails into the adjacent PET unit and scans were performed at exactly the same orientation. Once in the scanners, a fixed light from each machine shining on the subject’s forehead was used to further minimize variation in head position between scans. These measures allowed CT and PET images to be generated in virtually identical planes. The subjects first inhaled ‘“02 (for rCMR0,) or C150, (for rCBF) through a comfortable but tight-fitting face mask until a constant level of head counts of radioactivity was achieved. At this steady-state, scanning was begun and continued until a total count of about 10000000 (i.e., 1000 counts per pixel) was reached (typically about 5 min). Three arterial blood samples were taken during this time to obtain the input function of RI to the brain, blood gases and hematological indices. Protocol Each trial consisted of a resting C1502 (rCBF) study, followed by 150 (rCMR0,) study. The first was performed with the subjects at rest, meaning that they were asked to close their eyes and to relax as completely as possible without sleeping.
TABLE I Data on subjects PT
Age
.%2X
Diagnosis
Duration
Tremor
Aphasia
Paresis
AS LT SA TM KU YW KK TA TS KB TU MK MS
22 31 70 48 66 16 40 63 31 58 51 61 51
M
NORMAL VOLUNTEER NORMAL VOLUNTEER essential tremor essential tremor Parkinson’s L temp seizures subcort lymphoma R cerebellar met subcort glioma R frontal mass callosal glioma L subcort lymphoma distal ACA aneurysm
years years years years 8 months 3 months 3 months 2 years 4 months 6 months 4 months
yes yes
none none none none none none none none none
none none none none none none mild none none none mild
Duration
M M M M
= time from symptom
onset to PET study.
yes none none none none none none none none
yes yes
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Ambient sound was kept to a minimum. This was followed by study during a speech task, which consisted of the subject relating in detail all the events of the previous day, from awakening onwards, beginning just prior to data acquisition and continuing to the end of the trial (less than 8 min). Once the data were calculated to give maps of rCMRO,, the active and resting scans were analyzed and compared. The subjects were observed on closed-circuit television to insure the smooth performance of each task. The face mask was designed to provide minimal interference with speech, and all subjects were able to complete the trials, as verified by audiomonitoring. Subjects
15 PET trials were performed on 13 subjects, comprising 9 males and 4 females, with a mean age of 47 (16-70). All were right-handed. Every subject also underwent a CT scan at the time of testing. Three trials were performed on two normal subjects and 12 on 11 patients under the care of the Department of Neurological Surgery, Gunma University. Of the patients, 2 had some degree of language disturbance, while the remaining 9 had normal speech (Table I). Of the latter, only two had supratentorial cortical pathology, and both of these patients were neurologically intact. In fact, other than for tremor, all of these patients showed no or minimal neurological deficit. Informed consent for the examinations was obtained in every case. Analysis
Patterns of metabolic change were analyzed in two ways. First, ‘subtraction images’ were made, in which values from the resting scan were subtracted, pixel-by-pixel, from those in the active scan and displayed as a new ‘subtraction image’ (Fig. 1). Second, 53 standardized ‘regions of interest’ (ROIs) were created on the 7 images, based on a standard anatomical atlas (Matsui and Hirano, 1978) and on study of speech and related areas with CT (Gilbert et al., 1986), and mean values of metabolism within each ROI obtained and tabulated. Our quantitative analysis was focused on changes in regional metabolism (rCMR0,) rela-
TABLE II Mean increases in metabolism relative to the pons (%), for regions showing more than 4.5% increase in subjects with normal speech (volunteers and non-aphasic patients) Volunteers CEREBELLUM: left right
Patients
9.67 8.67
4.67 5.00
TEMPORAL (LEFT MEDIAL): hippocampus: anterior mid/posterior Wernicke’s
16.33 20.00 5.00
7.50 9.75 6.27
FRONTAL: left: opercular pre-motor right; opercular pre-motor
11.33 12.67 17.00 18.00
6.08 4.92 8.42 5.17
PARIETAL (RIGHT): inferior lobule superior lobule
9.33 11.33
5.17 4.92
5.33
4.92
SUPPLEMENTARY (RIGHT):
MOTOR
tive to the pons (100 X rCMR0, ROI/pons((active-rest)/rest), where ROI refers to the region of interest; the pons was in every case free of abnormality). This parameter served to emphasize regional activation, not masked by global metabolic changes. The linear correlation between changes in total brain metabolism and that in the pons was extremely high (I = 0.92, slope = 0.99). Analysis with normalization to global brain metabolism - a more time-consuming procedure - did not materially change the results.
RESULTS Average changes in metabolism with normal speech
On average, oxygen metabolism increased with the task by 7.7% and 7.9% in the left and right hemispheres, respectively. No significant hemispheric asymmetry developed in any of the subjects. A net decrease in mean CMRO, occurred in 12 of the 30 hemispheres studied. Table II shows those brain regions that underwent greater than 4.5% increase of relative
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metabolism with the task in normal volunteers and in patients without language disturbance. The greatest mean activation was found in left medial temporal lobe structures, followed closely by bilateral low frontal regions comprising Broca’s area
Fig. 1. Upper superimposing
and its contralateral homolog. Substantial increases also occurred in both pre-motor areas, cerebellar hemispheres and in the right parietal and supplementary motor areas. In comparison, Wernicke’s area showed lesser activation, while
right shows subtraction scan of metabolism (speaking-resting) for subject AS. By comparing (upper left) or (lower) PET image with identical CT slice, activated region can be clearly identified as Broca’s area (left side of brain is on left side of image).
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the lateral portion of the left temporal lobe in particular was one of the least active regions. The apparent greater degree of activation seen in normal volunteers may reflect the smaller number of subjects in this group. We also looked at activation patterns around Broca’s area in particular by reviewing subtraction images (Fig. 1). Activation related to speech in this area was found to be somewhat variable in extent, though focused on classical Broca’s area: in some subjects, active areas were very circumscribed and small; in others, more widespread and extending posteriorly to primary motor cortex and anteriorly to the low pre-frontal region, with most trials somewhere in between these extremes. Patterns in aphasic and other patients Both subjects with abnormal language function exhibited expressive aphasias (MK and MS). In neither was there significant metabolic activation of any traditional speech areas with the task. In one aphasic, this abnormality was uncovered only by the speech activation technique. Patient MS was a 51-year-old right-handed man who had undergone clipping of a distal right anterior cerebral artery aneurysm 4 months prior to study. This was followed by a delayed ischemic deficit, with transient left leg weakness and speech difficulty which evolved from mutism to slowed speech and moderate anomia over a two-week period. At the time of our examination, his speech was notable for circumlocution, perseveration and naming difficulties. His other residual deficits were a subtle left bradykinesia and a curious dysgraphia when using the right, but not the left hand. This applied to both Japanese kanji (pictoral) and kana (phonetic) symbols. Comprehension was normal. CT scan revealed old infarcts mainly in the right but also in the left mesial frontal regions, shown as well on the resting PET image of CBF. Metabolism and blood flow in Broca’s area, as elsewhere, were unremarkable. With the speech task, the structurally intact portions of both mesial hemispheres showed the expected significant increases in relative metabolism (8-10%). However, there was no activation of the left frontal or
temporal lobes. Furthermore, unlike the other aphasic subject (MK), the right frontal operculum also failed to be activated. The second patient (MK) was a 61-year-old right-handed man with lymphoma in the left basal ganglia region for which he had undergone radiation therapy 4 months prior to study. His examination revealed moderately slowed speech with anomia, but normal comprehension, present since his initial presentation. His CT showed no focal abnormality, while PET revealed widespread reduction in metabolism on the left side. There was virtually no activation of the left frontal or temporal lobes with speech, while of the other expected regions, only the right frontal operculum was clearly activated (12%). A third subject (YW) who performed the task normally nevertheless showed an unusual activation pattern with speech. This was a 16-year-old girl who had partial complex seizures for many years, associated with a large calcific mass in the mesial left temporal region. She was neurologitally normal between fits. PET at rest showed an area of low metabolism in the medial left temporal lobe adjacent to the mass. With speech, she was the only subject to show activation (over 5%) of the lateral part of a large portion of the left temporal lobe - an area with some of the least increase in all other subjects.
DISCUSSION Methodological considerations Studies of brain activation with various tasks may be of value in understanding not only normal physiology, but also pathophysiology. With this in mind, we have studied normal subjects, patients with no or minimal neurological signs, as well as those with aphasia. Many subjects with tremor (essential or Parkinsonian) were included because little or no abnormality of resting blood flow or metabolism has been found in these patients (Kuhl et al., 1984; Leenders et al., 1983; Rougemont et al., 1983), and because ours is a major referral center for these disorders. A ‘speech from memory’ task was chosen because it fulfilled two criteria: (11, it promised to
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activate many areas of the brain and (2), it is a natural, realistic and reliable task which can keep a subject’s interest and continuous performance for the duration of the trial. Previous PET studies of speech in normal subjects have focused on discrete linguistic tasks (Frith et al., 1991; Petersen et al., 1988) which activated restricted brain regions. In view of our heterogeneous study group, a task activating wider brain areas and easily performed by patients, as well as normal volunteers was chosen. The study of changes in regional brain metabolism with various tasks or stimuli has been well-established by several groups using PET (Kushner et al., 1987; Mazziotta et al., 1982, 1984). Correlation between glucose and oxygen metabolism measured by PET has been reasonably good (Hatazawa et al., 19881, but the shorter half-life of I50 allows for more efficient task studies. The choice of metabolism over blood flow as the target variable has been based on several considerations. Local metabolism is directly related to the actual (energy-dependent) performance of brain tissue, without intermediate mechanisms, such as autoregulation or distant neurovascular control intervening. This is particularly important in disease states, where these mechanisms may indeed be considerably altered (e.g., Wise et al., 1983). Most groups using PET to look at abnormal subjects have studied brain glucose (Metter et al., 1981, 1984, 1987, 1989) or oxygen (Tyrrell et al., 1990, 1991) metabolism. Fox and Raichle (1986) found larger local increases in blood flow than in metabolism with somatosensory stimulation in normal subjects, implying a further uncoupling of these two parameters under physiological conditions. However, this uncoupling has not been uniformly found in studies utilizing other techniques (Gregory et al., 19771, tasks (such as with movement (Raichle et al., 1976)) or subjects, and demonstration of this effect under the same conditions awaits replication. In addition, there is the possibility of error from variations in regional transit times and other factors (Koeppe et al., 1987). Study of regional brain activation in a mixed group of subjects such as ours precludes the use of statistical parametric mapping (Friston et al.,
1990) or other analytic techniques relying on inter-subject averaging (Fox et al., 1988). In view of this limitation to the present study, we have chosen to identify regions that showed increases in metabolism greater than the reproducibility of the I50 technique (between 4 and 5% (Frackowiak et al., 1980; Reivich et al., 1985; Wise et al,, 1983)). It remains an open question as to what a ‘significant change’ in metabolism really is in an individual subject, since changes may be due to technical factors, to noise in the system, or to deviations in subjects’ thought processes from that intended, over which there is little control. However, our finding that brain regions classically associated with speech and memory were activated in both normal volunteers and patients with intact speech, yet absent in patients with language deficit suggests the validity of this approach, at least to a first order of approximation. The normalization of regional metabolism to that of the brain as a whole has been shown to be a useful and valid technique for assessing regional activation (Fox et al., 19881, particularly when moderately large regions of interest are used (Friston et al., 19901, but again, previous studies have relied on interindividual averaging (Friston et al., 1991; Petersen et al., 1988) to achieve statistical power. Changes in relative metabolism may be more significant than those in absolute metabolism, particularly if the ‘global-independent’ component of the change is very small (approaching zero, see Friston et al., 19901. In analyzing patterns of regional brain activation, we chose to normalize to the pons because it is a heterogeneous brainstem structure that would not be expected to reflect lateralized or focal cortical processes, and because it is relatively easy to identify and measure on a single image. In view of the extremely close correlation found between changes in global metabolism and that of the pons, it was not surprising that the results were in essence the same no matter which factor was used. Changes in metabolism with speech task Our finding an average of 7.8% increase in global hemispheric metabolism with speech is strikingly similar to increases in CBF of 6% by
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Larsen et al. (1978) and 7.8% by Wallesch et al. (1985), who, like us, also found one-third of trials with an actual decline in global flow and no evidence of hemispheric lateralization. Using “O-PET Frith et al. (1991) also found a decline in global’ CBF with a speech task in 4 subjects. These global changes have been found with a variety of other tasks or complex stimuli (Gur et al., 1982; Nishizawa et al., 1982) and therefore cannot be said to be speech-specific. As to patterns of regional change, several groups have described activation of CBF with The speech using 133Xe and 150-PET techniques. study with a paradigm most resembling ours was that of Roland (19851, who asked subjects to name the furniture in their living rooms. His findings were strikingly similar to ours, with increases of CBF in both frontal opercular, pre-motor and supplementary motor areas, as well as in the left temporal and right parietal lobes. Comparison with other studies is limited by differences in the specific tasks used. Ingvar and Schwarz (1974), using a recitation task, showed similar activation in the left hemisphere, but without anterior or mid-temporal lobe activity. This was confirmed by Larsen et al. (1978) and extended by Ryding et al. (19871, using similar techniques and tasks. Wallesch et al. (1985) employed several tasks to identify the memory component of a speech-from-memory task. The left temporal lobe was specifically activated by the memory component of the tasks, but they could not determine exactly which portion was involved. More recently, Petersen et al. (1988) reported studies of regional CBF changes with speech using 150-PET. Their paradigm overlapped with ours only in that it involved speech, but from visual or auditory cues. They nevertheless found bilateral activation of the frontal opercular, mouth-motor and supplementary motor regions, as well as the left pre-motor area. In contrast to the present findings, there was no anterior temporal lobe activation, perhaps because their task had no memory component. However, the strong bilateral activation of the cerebellum found in the present study was subsequently described by this group in a later publication (Petersen et al., 1990). Finally, Frith et al. (1991) used several paradigms
to study changes in regional CBF specific to ‘intrinsic’ and ‘extrinsic’ aspects of speech. They found a region in the left dorsolateral frontal lobe (including pre-motor area) which was activated solely by internally generated speech. Based on the above studies, our finding of activation of the frontal opercular, pre-motor, cerebellar and supplementary motor areas likely relates to expressive speech processes, while activation of the medial left temporal lobe may have more to do with the memory or non-verbal component of the task. In interpreting these findings, it should be kept in mind that increases in regional CBF or CMR with speech may reflect inhibitory, as well as excitatory neural processes, since both require energy. Where the tasks overlap, the results of these studies agree to a large extent with traditional models of brain language organization, since classical language-related areas show some of the greatest and most consistent activations. However, recent studies would extend these models by recognizing the importance of the right frontal operculum, supplementary motor area and both cerebellar hemispheres in speech production. Stimulation of the first two of these areas in humans has been known for a long time to interrupt speech (Rasmussen and Milner, 1975). However, activation of the latter two regions may relate more to preparation or initiation of movement (Colebatch, Deiber et al., 19911, of which speech is a subset, or to diaphragmatic activation (Colebatch, Adams et al., 1991) rather than to language per se. With respect to bilaterality of activation of the frontal opercula, pre-motor and supplementary motor areas, the significance of this effect is unknown. While the right hemisphere is known to play a role in the affective and contextual aspects of speech (Heilman et al., 1986), there is no evidence that this role involves homologous structures on both sides. Cortical control of the diaphragm is known to be strongly lateralized (Colebatch, Adams et al., 19911, implying that the smooth diaphragmatic contractions necessary for speech require bilateral activation. Alternatively, metabolic activation of right-hemisphere regions may represent inhibitory processes. Since there is
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bilateral cortical control of the orofacial musculature, this inhibition may prevent activation of the orofacial apparatus by right-hemispheric nonspeech inputs during left-hemisphere controlled speech. Against this is that even unilateral finger movements are associated with widespread activation of homologous cortical structures (Roland et al., 1982).
Clinical aspects Several groups have studied resting cerebral metabolism with 18FDG (Chawluk et al., 1986; Metter et al., 1981, 1984, 1987, 1989) or I50 (Tyrrell et al., 1990, 1991) in patients with language deficits. A number of conclusions have emerged. The boundaries of metabolic abnormality (at rest) often exceed those of structural abnormality, as seen on CT (Metter et al., 1981, 1984) or MRI (Tyrrell et al., 1990). Metabolically abnormal areas distant from structural lesions were frequently found, such as the right cerebellum in patients with expressive aphasia (Metter et al., 1987). Subjects without any structural abnormality on CT or MRI may have significant abnormalities of resting metabolism or blood flow which could explain clinical speech deficits, particularly in slowly progressive aphasia (Chawluk et al., 1986; Tyrrell et al., 1990, 1991). Finally, patterns of metabolic abnormality often did not conform to specific types of language deficit as predicted from classical models of language localization (Metter et al., 1987, 1989). Soh et al. (1977) were the first to use an activation technique in abnormal subjects. They employed a speech task (counting) with ‘““Xe to study blood flow activation in the left hemisphere of 13 aphasic patients. These patients all had extensive lesions, as indicated by 11 of them also being hemiplegic, and all showed reduced left hemispheric blood flow at rest. Unfortunately, their brief report did not provide detailed information about patterns of regional activation. Two more recent investigators also utilized PET with task studies, both in dyslexic subjects. GrossGlenn et al. (1991) studied glucose metabolism with word reading and Rumsey et al. (1992) blood flow with rhyme detection. The latter study found
absence of left temporo-parietal activation in 14 dyslexics, in spite of normal resting blood flow and structure, showing the power of their activation technique. Neither of our two aphasic subjects showed activation of Broca’s area with the speech task. In addition, of the 11 other regions activated with speech in our non-aphasic subjects, only the cerebellar hemispheres (case MS) and the right frontal operculum (case MK) showed significantly increased metabolism. Neither patient had a structural abnormality of the left frontal operculum on CT, while one had normal resting CBF and CMRO, in that region as well (MS). This subject’s aphasia would have been difficult to explain had an activation technique not been employed. It is speculated that dysfunction of the supplementary motor area, whose role may include modulation of expressive speech centers, could explain his activation abnormality and speech deficit. This ‘diaschesis’ of metabolic activation would represent a mechanism whereby anatomically and physiologically normal regions of the brain may fail to be utilized properly by abnormal regions, giving rise to symptoms referable to the healthy areas. It has been hypothesized by Goldstein (1948) and others since then to explain the transcortical aphasias, though direct evidence for it has been lacking. Finally, there is the unusual left-lateral temporal lobe activation in the patient with epilepsy and a left-mesial temporal mass (YW). She was the only subject showing activation of the lateral portion of left temporal lobe. Based on cortical stimulation studies in patients with temporal lobe epilepsy, Ojemann and Dodrill (1985) suggested that the lateral aspect of the left temporal lobe may be of importance in short-term memory. Since the only subject in our series showing left lateral temporal activation also had temporal lobe epilepsy, we suspect that left lateral temporal lobe involvement with memory may be a compensatory rather than a normal physiological phenomenon. In conclusion, these results suggest that activation techniques utilizing PET can provide insight into not only the normal brain mechanisms of language, but also the pathophysiology of aphasias
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which, in some cases, may be otherwise difficult to understand.
ACKNOWLEDGEMENT We gratefully acknowledge the support of the Japan Society for the Promotion of Science.
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(1989) Cerebral glucose metabolism in Wernicke’s, Broca’s, and conduction aphasia. Arch. Neural., 46: 27-34. Metter, E.J., Kempler, D., Jackson, C.A., Hanson, W.R., et al. (1987) Cerebellar glucose metabolism in chronic aphasia. Neurology, 37: 1599-1606. Metter. E.J., Riege, W.H., Hanson, W.R., et al. (1984) Correlations of glucose metabolism and structural damage to language function in aphasia. Brain Lang., 21: 187-207. Metter, E.J., Wasterlain, C.G., Kuhl, D.E., et al. (1981) ‘xF.D.G positron emission computed tomography in a study of aphasia. Ann. Neural., 10: 173-183. Nishizawa, Y., Olsen, T.S., Larsen, B., et al. (1982) Left-right cortical asymmetries of regional cerebra1 blood flow during listening to words. L Neurophysiol., 48: 458-466. Ojemann, G.A. (1983) Brain organization for language from the perspective of electrical stimulation mapping. Behal’. Brain Sci., 6: 1899206. Ojemann, G.A. and Dodrill, C.B. (1982) Verbal memory deficits after left temporal lobectomy for epilepsy. J. Neurosurg., 62: 101~107. Petersen, S.E., Fox, P.T., Posner, MI., et al. (1988) Positron emission tomographic studies of the cortical anatomy of single-word processing. Nature, 331: 585-589. Petersen, S.E., Fox, P.T., Posner, MI., Mintun. M. and Raichle, M.E. (1990) Positron emission tomographic studies of the processing of single words. J. Cogn. Neurosci.. 1: 153-170. Raichle, M.E., Grubb, R.L., Gado, M.H., Eichling, J.O. and Ter-Pogossian, M.M. (1976) Correlation between regional cerebral blood flow and oxidative metabolism. Arch. Neurol., 33: 523-526. Rasmussen, T. and Milner, B (1975) Clinical and surgical studies of the cerebral speech areas in man. In Zulch, K.J.. Creutzfeldt, 0. and Galbraith, G.C. (Eds.), Cerebral localizafion, Springer, Berlin, pp. 2388257. Reivich, M., Alavi. A., Gur, R.C., et al. (1985) Determination of local cerebral glucose metabolism in humans: methodology and applications to the study of sensory and cognitive stimuli. In Sokoloff, L. (Ed.), Brain imaging and brain function, Raven, New York, pp. 105-119.
Roland, P.E. (1985) Applications of brain blood flow imaging in behavioral neurophysiology: cortical field activation hypothesis. In Sokoloff, L. (Ed.), Brain imaging and brain function, Raven, New York, pp. 87-103. Roland, P.E., Meyer, E.. Shibasaki, T., et al. (1982) Regional cerebra1 blood flow changes in cortex and basal ganglia during voluntary movements in normal human volunteers. J. Neurophysiol., 48: 467-80. Rougemont, D., Baron, J.C., Collard, P., et al. (1983) Local cerebral metabolic rate of glucose (IC.M.R.G.lc) in treated and untreated patients with Parkinson’s disease. J. Cerehr. Blood Flow Metab., 3 (Suppl. 1): 5044505. Rumsey, J.M., Andreason, P., Zametkin, A.J., Aquino, T., et al. (1992) Failure to activate the left temporoparietal cortex in dyslexia: An oxygen 15 positron emission tomographic study. Arch. Neural., 49: 527-534. Ryding, E., Bradvik, B. and Ingvar, D.H. (1987) Changes in regional cerebral blood flow measured simultaneously in the right and left hemisphere during automatic speech and humming. Brain, 110: 1345-1358. Soh, K., Larsen, B., Skinhoj, E., et al. (1977) rC.B.F in aphasia. Acta Neural. Scund., 56 (Suppl. 64): 270-271. Tyrrell, P.J., Kartsounis, L.D., Frackowiak, R.S.J., Findley, L.J. and Rossor, M.N. (1991) Progressive loss of speech output and orofacial dyspraxia associated with frontal lobe hypometabolism. J. Neural. Neurosurg. Psychiarr?,, 54: 351357. Tyrrell, P.J., Warrington, E.K., Frackowiak, R.S.J. and Rossor, M.N. (1990) Heterogeneity in progressive aphasia due to focal cortical atrophy: A clinical and P.E.T study. Brain, 113: 1321-1336. Wallesch, C.W., Henriksen, L., Kornhuber, H.H., et al. (1985) Observations on regional cerebral blood flow in cortical and subcortical structures during language production in normal man. Bruin Lang., 25: 224-233. Wise, R.J.S., Bernardi, S., Frackowiak, R.S., et al. (1983) Serial observations on the pathophysiology of acute stroke. The transition from ischemia to infarction as reflected in regional oxygen extraction. Bruin, 106: 197-222.
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General activation of cerebral metabolism with speech: a PET study Laszlo B. Tamas b, Takashi
Shibasaki
a, Satoru Horikoshi
a and Chihiro
Ohye a
a Department of Neurological Surgery, Gunma University School of Medicine, Maebashi-shi, Gunma-ken (Japan) and b Department of Neurological Surgery, University of California at Davis, Martinez, CA (USA) (Accepted
Key words: Speech;
28 September
Metabolism;
Emission
1992)
tomography;
Aphasia
We report the pattern of metabolic activation of the brain associated with speech, using I50 positron emission tomography (PET) in normal volunteers, as well as patients with or without language deficit. 15 trials were performed on 13 subjects. Regional oxygen metabolism with the subjects at rest was compared to that during a speech-from-memory task. As expected, there was strong activation of Broca’s area and the medial left temporal lobe, corresponding to the motor speech and memory aspects of the task. In addition, botb cerebellar hemispheres and pre-motor areas, as well as the right frontal operculum, supplementary motor area and right parietal lobe were active. This technique provided insight into the mechanism of aphasia in two subjects, even in one whose traditional language areas were structurally and metabolically intact at rest. We conclude that this practical activation technique may be useful not only in studying the physiology of normal brain, but also in understanding functional responses to
INTRODUCTION The first observations about lateralization and localization of function in the brain were made on the effects of experiments of nature such as head injuries, stroke and epilepsy. This led to the concepts of cerebral dominance and of receptive and expressive speech ‘centers.’ The limitations of these concepts were recognized by Hughlings Jackson, who wrote in 1874 that ‘to locate the damage which destroys speech and to locate speech are two different things’ (Jackson, 1874). Several recent lines of evidence suggest that cortical areas involved with speech may be more variable and widespread than previously thought.
Correspondence to: L.B. Tamas, Department of Neurological Surgery, University of California at Davis, V.A. Medical Center, 150 Muir Road, Martinez, CA 94553, USA.
Studies of patients with left hemispheric lesions using CT (Basso et al., 1985) or PET (Metter et al., 1984) imaging found a significant proportion of patients with speech deficits not explained by traditional language models. Cortical stimulation mapping has likewise revealed a much greater variability and wider distribution of language areas than expected (Ojemann, 1983). Finally, increases in cerebral blood flow with speech have been described not only in Broca’s area, but also in both pre-motor and supplementary motor areas and in the right frontal operculum (Friston et al., 1991; Larsen et al., 1978; Petersen et al., 1988; Roland, 1985). Positron emission tomography with 150 permits the study of regional metabolism and blood flow in the human brain during a variety of tasks. In a landmark study, Petersen et al. (1988) showed regional increases of cerebral blood flow specific for sensory, articulatory and semantic aspects of
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language in normal subjects. Using a similar technique, Frith et al. (1991) identified brain regions specifically involved in ‘intrinsic’ and ‘extrinsic’ word generation. Both groups employed statistical analytic techniques which required averaging regional changes among a group of normal subjects. However, because of the highly individual nature of clinical brain lesions, these techniques are difficult to apply with patients. The purposes of the present study were to simply observe patterns of regional brain activation associated with a speech task, and to determine if they could shed light on mechanisms of speech dysfunction in patients.
METHODS ‘SO-Positron emission tomography We have utilized the 150 continuous-inhalation method of Frackowiak et al. to determine regional cerebral oxygen metabolism (rCMR0,) and blood flow (rCBF), details of which have been described (Frackowiak et al., 1980). The Hitachi PCT H-l system was used, which employs 128 detectors, yielding a transverse resolution of 8 mm and slice thickness of 16 mm. I50 was generated in our facility by the Nippon Steel Works Ultramini Cyclotron. A germanium/gallium source was used for attenuation correction.
Each trial began with a CT scan, producing 7 brain images parallel to the orbitomeatal plane and extending upwards from the pons to the vertex. The subject’s bed was then moved on specially installed rails into the adjacent PET unit and scans were performed at exactly the same orientation. Once in the scanners, a fixed light from each machine shining on the subject’s forehead was used to further minimize variation in head position between scans. These measures allowed CT and PET images to be generated in virtually identical planes. The subjects first inhaled ‘“02 (for rCMR0,) or C150, (for rCBF) through a comfortable but tight-fitting face mask until a constant level of head counts of radioactivity was achieved. At this steady-state, scanning was begun and continued until a total count of about 10000000 (i.e., 1000 counts per pixel) was reached (typically about 5 min). Three arterial blood samples were taken during this time to obtain the input function of RI to the brain, blood gases and hematological indices. Protocol Each trial consisted of a resting C1502 (rCBF) study, followed by 150 (rCMR0,) study. The first was performed with the subjects at rest, meaning that they were asked to close their eyes and to relax as completely as possible without sleeping.
TABLE I Data on subjects PT
Age
.%2X
Diagnosis
Duration
Tremor
Aphasia
Paresis
AS LT SA TM KU YW KK TA TS KB TU MK MS
22 31 70 48 66 16 40 63 31 58 51 61 51
M
NORMAL VOLUNTEER NORMAL VOLUNTEER essential tremor essential tremor Parkinson’s L temp seizures subcort lymphoma R cerebellar met subcort glioma R frontal mass callosal glioma L subcort lymphoma distal ACA aneurysm
years years years years 8 months 3 months 3 months 2 years 4 months 6 months 4 months
yes yes
none none none none none none none none none
none none none none none none mild none none none mild
Duration
M M M M
= time from symptom
onset to PET study.
yes none none none none none none none none
yes yes
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Ambient sound was kept to a minimum. This was followed by study during a speech task, which consisted of the subject relating in detail all the events of the previous day, from awakening onwards, beginning just prior to data acquisition and continuing to the end of the trial (less than 8 min). Once the data were calculated to give maps of rCMRO,, the active and resting scans were analyzed and compared. The subjects were observed on closed-circuit television to insure the smooth performance of each task. The face mask was designed to provide minimal interference with speech, and all subjects were able to complete the trials, as verified by audiomonitoring. Subjects
15 PET trials were performed on 13 subjects, comprising 9 males and 4 females, with a mean age of 47 (16-70). All were right-handed. Every subject also underwent a CT scan at the time of testing. Three trials were performed on two normal subjects and 12 on 11 patients under the care of the Department of Neurological Surgery, Gunma University. Of the patients, 2 had some degree of language disturbance, while the remaining 9 had normal speech (Table I). Of the latter, only two had supratentorial cortical pathology, and both of these patients were neurologically intact. In fact, other than for tremor, all of these patients showed no or minimal neurological deficit. Informed consent for the examinations was obtained in every case. Analysis
Patterns of metabolic change were analyzed in two ways. First, ‘subtraction images’ were made, in which values from the resting scan were subtracted, pixel-by-pixel, from those in the active scan and displayed as a new ‘subtraction image’ (Fig. 1). Second, 53 standardized ‘regions of interest’ (ROIs) were created on the 7 images, based on a standard anatomical atlas (Matsui and Hirano, 1978) and on study of speech and related areas with CT (Gilbert et al., 1986), and mean values of metabolism within each ROI obtained and tabulated. Our quantitative analysis was focused on changes in regional metabolism (rCMR0,) rela-
TABLE II Mean increases in metabolism relative to the pons (%), for regions showing more than 4.5% increase in subjects with normal speech (volunteers and non-aphasic patients) Volunteers CEREBELLUM: left right
Patients
9.67 8.67
4.67 5.00
TEMPORAL (LEFT MEDIAL): hippocampus: anterior mid/posterior Wernicke’s
16.33 20.00 5.00
7.50 9.75 6.27
FRONTAL: left: opercular pre-motor right; opercular pre-motor
11.33 12.67 17.00 18.00
6.08 4.92 8.42 5.17
PARIETAL (RIGHT): inferior lobule superior lobule
9.33 11.33
5.17 4.92
5.33
4.92
SUPPLEMENTARY (RIGHT):
MOTOR
tive to the pons (100 X rCMR0, ROI/pons((active-rest)/rest), where ROI refers to the region of interest; the pons was in every case free of abnormality). This parameter served to emphasize regional activation, not masked by global metabolic changes. The linear correlation between changes in total brain metabolism and that in the pons was extremely high (I = 0.92, slope = 0.99). Analysis with normalization to global brain metabolism - a more time-consuming procedure - did not materially change the results.
RESULTS Average changes in metabolism with normal speech
On average, oxygen metabolism increased with the task by 7.7% and 7.9% in the left and right hemispheres, respectively. No significant hemispheric asymmetry developed in any of the subjects. A net decrease in mean CMRO, occurred in 12 of the 30 hemispheres studied. Table II shows those brain regions that underwent greater than 4.5% increase of relative
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metabolism with the task in normal volunteers and in patients without language disturbance. The greatest mean activation was found in left medial temporal lobe structures, followed closely by bilateral low frontal regions comprising Broca’s area
Fig. 1. Upper superimposing
and its contralateral homolog. Substantial increases also occurred in both pre-motor areas, cerebellar hemispheres and in the right parietal and supplementary motor areas. In comparison, Wernicke’s area showed lesser activation, while
right shows subtraction scan of metabolism (speaking-resting) for subject AS. By comparing (upper left) or (lower) PET image with identical CT slice, activated region can be clearly identified as Broca’s area (left side of brain is on left side of image).
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the lateral portion of the left temporal lobe in particular was one of the least active regions. The apparent greater degree of activation seen in normal volunteers may reflect the smaller number of subjects in this group. We also looked at activation patterns around Broca’s area in particular by reviewing subtraction images (Fig. 1). Activation related to speech in this area was found to be somewhat variable in extent, though focused on classical Broca’s area: in some subjects, active areas were very circumscribed and small; in others, more widespread and extending posteriorly to primary motor cortex and anteriorly to the low pre-frontal region, with most trials somewhere in between these extremes. Patterns in aphasic and other patients Both subjects with abnormal language function exhibited expressive aphasias (MK and MS). In neither was there significant metabolic activation of any traditional speech areas with the task. In one aphasic, this abnormality was uncovered only by the speech activation technique. Patient MS was a 51-year-old right-handed man who had undergone clipping of a distal right anterior cerebral artery aneurysm 4 months prior to study. This was followed by a delayed ischemic deficit, with transient left leg weakness and speech difficulty which evolved from mutism to slowed speech and moderate anomia over a two-week period. At the time of our examination, his speech was notable for circumlocution, perseveration and naming difficulties. His other residual deficits were a subtle left bradykinesia and a curious dysgraphia when using the right, but not the left hand. This applied to both Japanese kanji (pictoral) and kana (phonetic) symbols. Comprehension was normal. CT scan revealed old infarcts mainly in the right but also in the left mesial frontal regions, shown as well on the resting PET image of CBF. Metabolism and blood flow in Broca’s area, as elsewhere, were unremarkable. With the speech task, the structurally intact portions of both mesial hemispheres showed the expected significant increases in relative metabolism (8-10%). However, there was no activation of the left frontal or
temporal lobes. Furthermore, unlike the other aphasic subject (MK), the right frontal operculum also failed to be activated. The second patient (MK) was a 61-year-old right-handed man with lymphoma in the left basal ganglia region for which he had undergone radiation therapy 4 months prior to study. His examination revealed moderately slowed speech with anomia, but normal comprehension, present since his initial presentation. His CT showed no focal abnormality, while PET revealed widespread reduction in metabolism on the left side. There was virtually no activation of the left frontal or temporal lobes with speech, while of the other expected regions, only the right frontal operculum was clearly activated (12%). A third subject (YW) who performed the task normally nevertheless showed an unusual activation pattern with speech. This was a 16-year-old girl who had partial complex seizures for many years, associated with a large calcific mass in the mesial left temporal region. She was neurologitally normal between fits. PET at rest showed an area of low metabolism in the medial left temporal lobe adjacent to the mass. With speech, she was the only subject to show activation (over 5%) of the lateral part of a large portion of the left temporal lobe - an area with some of the least increase in all other subjects.
DISCUSSION Methodological considerations Studies of brain activation with various tasks may be of value in understanding not only normal physiology, but also pathophysiology. With this in mind, we have studied normal subjects, patients with no or minimal neurological signs, as well as those with aphasia. Many subjects with tremor (essential or Parkinsonian) were included because little or no abnormality of resting blood flow or metabolism has been found in these patients (Kuhl et al., 1984; Leenders et al., 1983; Rougemont et al., 1983), and because ours is a major referral center for these disorders. A ‘speech from memory’ task was chosen because it fulfilled two criteria: (11, it promised to
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activate many areas of the brain and (2), it is a natural, realistic and reliable task which can keep a subject’s interest and continuous performance for the duration of the trial. Previous PET studies of speech in normal subjects have focused on discrete linguistic tasks (Frith et al., 1991; Petersen et al., 1988) which activated restricted brain regions. In view of our heterogeneous study group, a task activating wider brain areas and easily performed by patients, as well as normal volunteers was chosen. The study of changes in regional brain metabolism with various tasks or stimuli has been well-established by several groups using PET (Kushner et al., 1987; Mazziotta et al., 1982, 1984). Correlation between glucose and oxygen metabolism measured by PET has been reasonably good (Hatazawa et al., 19881, but the shorter half-life of I50 allows for more efficient task studies. The choice of metabolism over blood flow as the target variable has been based on several considerations. Local metabolism is directly related to the actual (energy-dependent) performance of brain tissue, without intermediate mechanisms, such as autoregulation or distant neurovascular control intervening. This is particularly important in disease states, where these mechanisms may indeed be considerably altered (e.g., Wise et al., 1983). Most groups using PET to look at abnormal subjects have studied brain glucose (Metter et al., 1981, 1984, 1987, 1989) or oxygen (Tyrrell et al., 1990, 1991) metabolism. Fox and Raichle (1986) found larger local increases in blood flow than in metabolism with somatosensory stimulation in normal subjects, implying a further uncoupling of these two parameters under physiological conditions. However, this uncoupling has not been uniformly found in studies utilizing other techniques (Gregory et al., 19771, tasks (such as with movement (Raichle et al., 1976)) or subjects, and demonstration of this effect under the same conditions awaits replication. In addition, there is the possibility of error from variations in regional transit times and other factors (Koeppe et al., 1987). Study of regional brain activation in a mixed group of subjects such as ours precludes the use of statistical parametric mapping (Friston et al.,
1990) or other analytic techniques relying on inter-subject averaging (Fox et al., 1988). In view of this limitation to the present study, we have chosen to identify regions that showed increases in metabolism greater than the reproducibility of the I50 technique (between 4 and 5% (Frackowiak et al., 1980; Reivich et al., 1985; Wise et al,, 1983)). It remains an open question as to what a ‘significant change’ in metabolism really is in an individual subject, since changes may be due to technical factors, to noise in the system, or to deviations in subjects’ thought processes from that intended, over which there is little control. However, our finding that brain regions classically associated with speech and memory were activated in both normal volunteers and patients with intact speech, yet absent in patients with language deficit suggests the validity of this approach, at least to a first order of approximation. The normalization of regional metabolism to that of the brain as a whole has been shown to be a useful and valid technique for assessing regional activation (Fox et al., 19881, particularly when moderately large regions of interest are used (Friston et al., 19901, but again, previous studies have relied on interindividual averaging (Friston et al., 1991; Petersen et al., 1988) to achieve statistical power. Changes in relative metabolism may be more significant than those in absolute metabolism, particularly if the ‘global-independent’ component of the change is very small (approaching zero, see Friston et al., 19901. In analyzing patterns of regional brain activation, we chose to normalize to the pons because it is a heterogeneous brainstem structure that would not be expected to reflect lateralized or focal cortical processes, and because it is relatively easy to identify and measure on a single image. In view of the extremely close correlation found between changes in global metabolism and that of the pons, it was not surprising that the results were in essence the same no matter which factor was used. Changes in metabolism with speech task Our finding an average of 7.8% increase in global hemispheric metabolism with speech is strikingly similar to increases in CBF of 6% by
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Larsen et al. (1978) and 7.8% by Wallesch et al. (1985), who, like us, also found one-third of trials with an actual decline in global flow and no evidence of hemispheric lateralization. Using “O-PET Frith et al. (1991) also found a decline in global’ CBF with a speech task in 4 subjects. These global changes have been found with a variety of other tasks or complex stimuli (Gur et al., 1982; Nishizawa et al., 1982) and therefore cannot be said to be speech-specific. As to patterns of regional change, several groups have described activation of CBF with The speech using 133Xe and 150-PET techniques. study with a paradigm most resembling ours was that of Roland (19851, who asked subjects to name the furniture in their living rooms. His findings were strikingly similar to ours, with increases of CBF in both frontal opercular, pre-motor and supplementary motor areas, as well as in the left temporal and right parietal lobes. Comparison with other studies is limited by differences in the specific tasks used. Ingvar and Schwarz (1974), using a recitation task, showed similar activation in the left hemisphere, but without anterior or mid-temporal lobe activity. This was confirmed by Larsen et al. (1978) and extended by Ryding et al. (19871, using similar techniques and tasks. Wallesch et al. (1985) employed several tasks to identify the memory component of a speech-from-memory task. The left temporal lobe was specifically activated by the memory component of the tasks, but they could not determine exactly which portion was involved. More recently, Petersen et al. (1988) reported studies of regional CBF changes with speech using 150-PET. Their paradigm overlapped with ours only in that it involved speech, but from visual or auditory cues. They nevertheless found bilateral activation of the frontal opercular, mouth-motor and supplementary motor regions, as well as the left pre-motor area. In contrast to the present findings, there was no anterior temporal lobe activation, perhaps because their task had no memory component. However, the strong bilateral activation of the cerebellum found in the present study was subsequently described by this group in a later publication (Petersen et al., 1990). Finally, Frith et al. (1991) used several paradigms
to study changes in regional CBF specific to ‘intrinsic’ and ‘extrinsic’ aspects of speech. They found a region in the left dorsolateral frontal lobe (including pre-motor area) which was activated solely by internally generated speech. Based on the above studies, our finding of activation of the frontal opercular, pre-motor, cerebellar and supplementary motor areas likely relates to expressive speech processes, while activation of the medial left temporal lobe may have more to do with the memory or non-verbal component of the task. In interpreting these findings, it should be kept in mind that increases in regional CBF or CMR with speech may reflect inhibitory, as well as excitatory neural processes, since both require energy. Where the tasks overlap, the results of these studies agree to a large extent with traditional models of brain language organization, since classical language-related areas show some of the greatest and most consistent activations. However, recent studies would extend these models by recognizing the importance of the right frontal operculum, supplementary motor area and both cerebellar hemispheres in speech production. Stimulation of the first two of these areas in humans has been known for a long time to interrupt speech (Rasmussen and Milner, 1975). However, activation of the latter two regions may relate more to preparation or initiation of movement (Colebatch, Deiber et al., 19911, of which speech is a subset, or to diaphragmatic activation (Colebatch, Adams et al., 1991) rather than to language per se. With respect to bilaterality of activation of the frontal opercula, pre-motor and supplementary motor areas, the significance of this effect is unknown. While the right hemisphere is known to play a role in the affective and contextual aspects of speech (Heilman et al., 1986), there is no evidence that this role involves homologous structures on both sides. Cortical control of the diaphragm is known to be strongly lateralized (Colebatch, Adams et al., 19911, implying that the smooth diaphragmatic contractions necessary for speech require bilateral activation. Alternatively, metabolic activation of right-hemisphere regions may represent inhibitory processes. Since there is
206
bilateral cortical control of the orofacial musculature, this inhibition may prevent activation of the orofacial apparatus by right-hemispheric nonspeech inputs during left-hemisphere controlled speech. Against this is that even unilateral finger movements are associated with widespread activation of homologous cortical structures (Roland et al., 1982).
Clinical aspects Several groups have studied resting cerebral metabolism with 18FDG (Chawluk et al., 1986; Metter et al., 1981, 1984, 1987, 1989) or I50 (Tyrrell et al., 1990, 1991) in patients with language deficits. A number of conclusions have emerged. The boundaries of metabolic abnormality (at rest) often exceed those of structural abnormality, as seen on CT (Metter et al., 1981, 1984) or MRI (Tyrrell et al., 1990). Metabolically abnormal areas distant from structural lesions were frequently found, such as the right cerebellum in patients with expressive aphasia (Metter et al., 1987). Subjects without any structural abnormality on CT or MRI may have significant abnormalities of resting metabolism or blood flow which could explain clinical speech deficits, particularly in slowly progressive aphasia (Chawluk et al., 1986; Tyrrell et al., 1990, 1991). Finally, patterns of metabolic abnormality often did not conform to specific types of language deficit as predicted from classical models of language localization (Metter et al., 1987, 1989). Soh et al. (1977) were the first to use an activation technique in abnormal subjects. They employed a speech task (counting) with ‘““Xe to study blood flow activation in the left hemisphere of 13 aphasic patients. These patients all had extensive lesions, as indicated by 11 of them also being hemiplegic, and all showed reduced left hemispheric blood flow at rest. Unfortunately, their brief report did not provide detailed information about patterns of regional activation. Two more recent investigators also utilized PET with task studies, both in dyslexic subjects. GrossGlenn et al. (1991) studied glucose metabolism with word reading and Rumsey et al. (1992) blood flow with rhyme detection. The latter study found
absence of left temporo-parietal activation in 14 dyslexics, in spite of normal resting blood flow and structure, showing the power of their activation technique. Neither of our two aphasic subjects showed activation of Broca’s area with the speech task. In addition, of the 11 other regions activated with speech in our non-aphasic subjects, only the cerebellar hemispheres (case MS) and the right frontal operculum (case MK) showed significantly increased metabolism. Neither patient had a structural abnormality of the left frontal operculum on CT, while one had normal resting CBF and CMRO, in that region as well (MS). This subject’s aphasia would have been difficult to explain had an activation technique not been employed. It is speculated that dysfunction of the supplementary motor area, whose role may include modulation of expressive speech centers, could explain his activation abnormality and speech deficit. This ‘diaschesis’ of metabolic activation would represent a mechanism whereby anatomically and physiologically normal regions of the brain may fail to be utilized properly by abnormal regions, giving rise to symptoms referable to the healthy areas. It has been hypothesized by Goldstein (1948) and others since then to explain the transcortical aphasias, though direct evidence for it has been lacking. Finally, there is the unusual left-lateral temporal lobe activation in the patient with epilepsy and a left-mesial temporal mass (YW). She was the only subject showing activation of the lateral portion of left temporal lobe. Based on cortical stimulation studies in patients with temporal lobe epilepsy, Ojemann and Dodrill (1985) suggested that the lateral aspect of the left temporal lobe may be of importance in short-term memory. Since the only subject in our series showing left lateral temporal activation also had temporal lobe epilepsy, we suspect that left lateral temporal lobe involvement with memory may be a compensatory rather than a normal physiological phenomenon. In conclusion, these results suggest that activation techniques utilizing PET can provide insight into not only the normal brain mechanisms of language, but also the pathophysiology of aphasias
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which, in some cases, may be otherwise difficult to understand.
ACKNOWLEDGEMENT We gratefully acknowledge the support of the Japan Society for the Promotion of Science.
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