VOL. 16, NO. 2, 1990
Gender Differences in Regional Cerebral Blood Flow
by Raquel E. Gur and Ruben C. Gur
Abstract
for measuring rCBF, then summarize the literature pertaining to gender differences, and finally discuss studies that examined gender differences in rCBF associated with schizophrenia. The
133
Xe Method
All current isotopic techniques for measuring cerebral metabolism and blood flow can be traced to the pioneering work of Kety and Schmidt (1948), who described a method for measuring whole-brain metabolism and blood flow. Their use of nitrous oxide and measurement of arterial-venous differences in concentration yielded accurate and reproducible data. However, this technique is not only limited to providing whole-brain values, but also is invasive, requiring catheterization of the carotid artery. Safe regional measurements of rCBF were first made possible by the introduction of the 133Xe clearance techniques. The highly diffusible 133Xe gas is administered either mixed in air for inhalation or in saline for intravenous infusion. Its clearance from the brain can be measured by stationary scintillation detectors. The rate of clearance enables quite accurate quantitation of rCBF in the fast-clearing gray matter compartment, as well as calculation of mean flow of gray and white matter. Initial applications used carotid injections (Olesen et al. 1971), which were invasive and only enabled measurements in one hemisphere at a time. In 1975, Obrist et al. (1975) and Risberg et al. (1975)
The application of techniques for measuring regional cerebral blood flow (rCBF) to the study of brain function provides the means to assess physiological concomitants of brain activity. In combination with task performance, which is introduced as a challenge, this research paradigm is the most direct avenue to investigate brain-behavior relationships. Gender is a major moderating variable in brain function, and hence it is not surprising that when sex differences in rCBF were examined, they were substantial. Since there are sex differences in psychopathology, as documented extensively in this issue of the Schizophrenia Bulletin, it is interesting to examine whether these may have substrates in regional brain physioReprint requests should be sent to Dr. logical activity reflected in rCBF. In R.E. Gur, University of Pennsylvania, this article we first present the Brain Behavior Laboratory, 205 Piersol 133 xenon (133Xe) inhalation method Bldg., Philadelphia, PA 19104.
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Gender differences have been noted in neurobehavioral studies. The "'xenon inhalation method for measuring regional cerebral blood flow (rCBF) can contribute to the understanding of the neural basis of gender differences in brain function. Few studies have examined gender differences in rCBF. In studies of normal subjects, women have higher rates of CBF than men, and this is related to age. Usually by the sixth decade men and women have similar flow rates. Fewer studies on rCBF in schizophrenia have examined sex differences. The pattern of higher flows for females maintains, but its correlates with gender differences in clinical as well as other parameters of brain function remain to be examined.
247
SCHIZOPHRENIA BULLETIN
248
duced that enables the placement of up to 254 detectors. The quantitative data can be displayed topographically (see figure 1). Note that rCBF is typically higher in the front of the brain. This "hyperfrontal" pattern has been observed routinely in normal subjects (Ingvar 1979). The main limitation of the technique is that it is optimal for measuring rCBF only on the brain surface near the skull, and hence it can be used to study primarily cortical brain regions.
Figure 1. Topographic display of regional CBF in a group of normal males (upper row) and females (lower row) during rest (column 1), a verbal analogies task (column 2), and a spatial line orientation task (column 3)
This method has been applied to many clinical populations, and normative data are extensive. In a challenge paradigm, subjects are engaged in a specific task during the period of measurement. We have used a repeated-measures design, where each participant undergoes three blood flow measurements, each lasting 15 minutes, in a single session. The tasks are presented in a counterbalanced order to control for the potential effect of factors such as novelty, anxiety, and fatigue. To measure hemispheric functioning, subjects are presented with a verbal task (analogies) and with a spatial task (line orientation), and rCBF is obtained during problem solving. Other tasks can be presented, depending on the hypotheses to be tested. Gender Differences in rCBF in Normal Subjects
Note the hyperfrontal pattern at rest, the higher cerebral blood flow (CBF) in females, and the increased CBF in the left for the verbal task and the right for the spatial task.
Despite the extensive literature on rCBF and on gender differences in brain function, only a few studies have examined gender differences in rCBF. We have measured rCBF in a sample of 62 young normals, 30 males and 32 females, with the cognitive activation paradigm described above. As can be seen in figure 2, blood flow rates were higher in females than in males (F = 15.55; df = 1,58; p < 0.001). Gender differences in the magnitude of 15 percent were evident for the initial slope (IS) index of gray matter flow as well as for all other indices. This difference, which existed for right-handers (n = 30) and left-handers (n = 32) at rest and during performance of both tasks, was significant for every detector. The effect did not diminish when factors which might influence rCBF
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
reported the 133Xe inhalation technique, and presented models for quantifying rCBF with this noninvasive procedure. The technique permits simultaneous measurements from both hemispheres, and the number of brain regions that can be measured depends on the number of detectors. Initial studies were performed with up to 16 detectors, 8 over each hemisphere, but there are now commercially available systems with 32 detectors and recently a system has been intro-
249
VOL. 16, NO. 2, 1990
Figure 2. Initial slope index of blood flow to the left (solid line) and right (dashed line) hemispheres in right- and left-handed males and females during 3 conditions1 Right-handers
Left-handers
o •o o o
X
80
•o
c
©
a o = c
7 0
I
_L R
V
S
R
V
S
R
V
S
Females (O). Males (D) Resting state (R) Verbal task (V). Spatial task (S) 'Reprinted, with permission, from Gur et al. (1982). Copyright © American Association for the Advancement of Science, 1982.
were considered: hemoglobin, diastolic and systolic blood pressure, and the partial pressure of CO2. In an extended sample (Gur et al. 1987b) of 55 right-handers, aged 18 to 72 years, subjects were divided into three age groups balanced for sex (< 20, 20-30, and > 30). As can be seen in figure 3, females had higher flows in all three groups, though the difference was most marked for the youngest group. A similar pattern of results was obtained in a subsequent study (Gur et al. 1988) where the effects of task difficulty on rCBF were examined
in relationship to anxiety and performance in 14 men and 12 women. Again, females had significantly higher rCBF. Shaw et al. (1984) examined CBF changes in benign aging in a sample of 130 normal subjects. While significantly higher gray matter flows were observed in women (« = 76) relative to men (n = 54) in the fourth to sixth decades, the gender difference was not significant after the sixth decade. A sample of 39 women was compared to 16 men by Davis et al. (1983), and the results reported were similar to those observed in the
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Total sample 90 r
studies above. Mean cerebral gray matter flow was higher in women in the second to fourth decades but not thereafter. More recently, Rodriguez et al. (1988) compared 38 men and 38 women who ranged in age from 18 to 72 years. An 11 percent increase in flow was evident in women across age groups with more symmetrical flows than seen in men. It should be noted that some studies reported no gender differences in CBF (Melamed et al. 1980; Hannay et al. 1983). The basis for higher flows in women is not clear. A number of factors might explain the gender differences. While the most obvious influence of blood pressure and p CO2 do not appear to affect the results obtained, other systemic factors might mediate. Shaw et al. (1984) suggested that low blood viscosity associated with menstruation might result in higher blood flow. CBF is affected by whole blood viscosity (Ott et al. 1985), and hemoglobin is correlated with oxygen-carrying capacity and inversely with CBF (Brown and Marshall 1985). However, Gur et al. (1982) could not account for the differences in CBF between males and females on the basis of hemoglobin. Furthermore, cerebral metabolism should not be affected by oxygen-carrying capacity, yet females have higher glucose metabolism (Baxter et al. 1987; Yoshii et al. 1988). It is possible the endocrine factors moderate the relationship with CBF and metabolism, and the effect of estrogen remains to be examined systematically. Other possible systemic factors that might contribute to the physiological differences in brain function are heart rate, pulse pressure, and cardiac index, which are higher in females than in males (Messerli et al. 1987). These will
250
Figure 3. Hemispheric cerebral blood flow for resting (R), verbal (V), and spatial (S) conditions for the 3 age groups1
lead to higher body blood flow, including brain, in women. Another potential explanation relates to differences in brain size between the genders (Buerger 1960). Thus, females have a higher rate of blood flow and metabolism, per 100 grams of brain tissue, to compensate for lower brain volume. This possibility was examined in a positron emission tomography study by Hatazawa et al. (1987), where women had a 9 percent increase in metabolism and 9 percent lower brain size, compared to men. A recent study from our laboratory suggests that the gender differences exist not only in absolute values of rCBF, but also in rCBF measures of habituation. Warach et al. (1987) examined the effects of repeated resting rCBF measurement in a sample of young men and women. For the whole sample, there was no significant difference between first and second resting measures, whether administered at the beginning of a session (before activation procedures were applied) or later on. Indeed, the reliability of rCBF measures with the 1MXe technique was exceedingly high, with correlations ranging from 0.86 to 0.97 for flow indices. However, there was a significant Order x Sex group interaction. Repeated initial studies showed reduced CBF from the first to the second resting measurement, but no reduction when the two resting measures were taken later in the series of studies (e.g., when the first two measures were obtained during task performance). The interaction with gender indicated that reduced CBF in serial measures was more pronounced in females. This finding is similar to effects reported for other neurophysiological measures of habituation, and it underscores the importance of
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Solid lines = left hemisphere. Dashed lines = right hemisphere. Triangles = men. Circles = women. 'Reprinted, with permission, from Gur et al. (1987a). Copyright © American Medical Association, 1987.
SCHIZOPHRENIA BULLETIN
251
VOL. 16, NO. 2, 1990
Gender Differences in rCBF in Schizophrenia As in normal controls, most rCBF studies in schizophrenia were conducted as resting flows, and gender differences were not examined. Using the activation paradigm described above, we have compared a sample of 7 men and 8 women with schizophrenia to 11 men and 14 women healthy controls. Patients were on neuroleptic medications during the time of study. The interaction of Diagnosis x Sex x Task was significant (F = 4.08; df = 2,72; p < 0.02). As can be seen in figure 4, women with schizophrenia had a different pattern of rCBF during task performance than all other groups. They showed little change in CBF during cognitive activation with the greatest increase for the verbal task, whereas the other groups showed increased flow for both tasks, with the greatest increase for the spatial task. Age, clinical subtypes, and severity of illness did not alter the pattern observed. In a subsequent study, patients (11 men, 8 women) were evaluated off neuroleptics and
Figure 4. Mean changes in regional cerebral blood flow for schizophrenic and matched control subjects divided by sex1 80
80
Men
ID O |
Women
75
75
70
70
65
65
o c CO
!s
0 — -O Schizophrenics Normal Controls I
I
R = resting state. V = solving verbal analogies. S = performing spatial task. 'Reprinted, with permission, from Gur et al. (1983). Copyright © American Medical Association, 1983.
compared to 11 men and 8 women control subjects. As can be seen in figure 5, gender is one of the factors that contributed to the abnormal pattern of rCBF in schizophrenia. Males with schizophrenia show higher left hemispheric flows in anterior brain regions both at rest and during the performance of the verbal task. Furthermore, unlike controls who for the spatial task had the highest flows, with the right hemisphere showing greater perfu-
sion than the left, patients had lower flows for the spatial task, relative to the verbal task, with no evidence of hemispheric specialization. Females with schizophrenia differed from control females both in anterior and posterior brain regions. Anteriorly, they had less increase for the spatial task, whereas posteriorly they showed higher left hemispheric flows for all three conditions, failing to demonstrate hemispheric specialization.
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
controlling for habituation effects on serial measurements of rCBF and metabolism. Considering gender differences neurobehaviorally, and the possible other explanations stated above, can lead to a series of studies that may elucidate the mechanisms underlying sex differences in brain function. These are testable hypotheses that can be addressed systematically. They can shed light not only on variability in normal brain function, but also in pathological conditions where gender differences have been noted.
252
SCHIZOPHRENIA BULLETIN
Figure 5. Hemispheric flows for resting (R), verbal (V), and spatial (S) conditions in anterior (precentral) and posterior (postcentrai) brain regions of schizophrenic and matched control subjects1
Conclusions
£ 60
Normal Schizophrenic I Left Hemisphere - I Right Hemisphere
55 R V S Anterior
R V S Posterior
R V S Anterior
R V S Posterior
'Reprinted, with permission, from Gur et al. (1985). Copyright © American Medical Association, 1985.
Ariel et al. (1983) obtained resting flows in patients (21 males, 8 females) and controls (14 males, 8 females) and reported that sex was not a factor contributing to the diagnostic group differences. Guenther et al. (1986) compared a sample of 16 patients with schizophrenia (10 males, 6 females) to 16 patients (6 males, 10 females) with endogenous depression and 8 (5 males, 3 females) controls. The authors state that the small number of subjects in each group did not permit exploring sex differences in detail, but comparison among male
and female subgroups did not indicate gender differences in the major findings of the study. Mathew et al. (1988) measured resting flows in 108 patients (60 males, 48 females) and 108 controls with the same gender distribution. Females, whether patients or controls, had higher CBF. These studies are quite preliminary. In addition to the potential factors that are likely to contribute to gender differences in CBF in normal subjects, other variables should be considered in the study of schizophrenia. These factors relate
Although gender differences in brain function have been examined neurobehaviorally, relatively few studies have focused on physiological measurements that might underlie these gender differences. Most studies that examined gender differences with the 133Xe inhalation method found that women had higher flows than men. These differences appeared to decline with aging. Many factors can potentially account for this observation. The research on schizophrenia is meager as far as the examination of gender differences in blood flow. It appears that female patients have higher flows than males, and further investigation of the pattern at activation is indicated. While efforts are devoted to the understanding of gender differences in normal brain function, studies in schizophrenia also need to pay attention to clinical variables where gender differences emerge. The tools are now available to relate clinical dimensions to neurobehavioral, neuroanatomical, and neurophysiological indices of brain function. This effort is likely to contribute to the understanding of the neurobiology of schizophrenia.
References Ariel, N.R.; Golden, C.J.; Berg, R. A.; Quaife, M.A.; Dirksen, J.W.; Forsell, T; Wilson, J.; and Graber, B. Regional cerebral blood flow in schizophrenics: Tests using the
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Women
Men
80
to differences in presentation and course of the disorder, and they require special attention in the experimental design and data analysis.
VOL. 16, NO. 2, 1990
Brown, M.M., and Marshall, J. Regulation of cerebral blood flow in response to changes in blood viscosity. Lancet, 1:604-609, 1985. Buerger, M. Altern und Krankeit als Problem der Biomorphose. Leipzig: Thieme, 1960. Davis, S.M.; Ackerman, R.H.; Correia, J.A.; Alpert, N.M.; Chang, ].; Buonanno, R.; Kelley, R.E.; Rosner, B.; and Taveras, J.M. Cerebral blood flow and cerebrovascular CO2 reactivity in stroke-age normal controls. Neurology, 33:391-399, 1983. Guenther, W.; Moser, E.; MuellerSpahn, R; von Oefele, K.; Buell, U.; and Hippius, H. Pathological cerebral blood flow during motor function in schizophrenic and endogenous depressed patients. Biological Psychiatry, 21:889-899, 1986. Gur, R.C.; Gur, R.E.; Obrist, W.D.; Hungerbuhler, J.P.; Younkin, D.; Rosen, A.D.; Skolnick, B.E.; and Reivich, M. Sex and handedness differences in cerebral blood flow during rest and cognitive activity. Science, 217:256-261, 1982. Gur, R.C.; Gur, R.E.; Obrist, W.D.; Skolnick, B.E.; and Reivich, M. Age and regional cerebral blood flow at rest and during cognitive activity. Archives of General Psychiatry, 44:617-621, 1987a. Gur, R.C.; Gur, R.E.; Resnick, S.M.; Skolnick, B.E.; Alavi, A.; and
Reivich, M. The effect of anxiety on cortical cerebral blood flow and metabolism. Journal of Cerebral Blood Flow and Metabolism, 7:173-177, 1987b. Gur, R.C.; Gur, R.E.; Skolnick, B.E.; Resnick, S.M.; Silver, F.L.; Chawluk, J.B.; Muenz, L.; Obrist, W.D.; and Reivich, M. Effects of task difficulty on regional cerebral blood flow: Relationships with anxiety and performance. Psychophysiology, 25:392-399, 1988. Gur, R.E.; Gur, R.C.; Skolnick, B.E.; Caroff, S.; Obrist, W.D.; Resnick, S.; and Reivich, M. Brain function in psychiatric disorders: III. Regional cerebral blood flow in unmedicated schizophrenics. Archives of General Psychiatry, 42:329-334, 1985. Gur, R.E.; Skolnick, B.E.; Gur, R.C.; Caroff, S.; Rieger, W.; Obrist, W.D; Younkin, D.; and Reivich, M. Brain function in psychiatric disorders: I. Regional cerebral blood flow in medicated schizophrenics. Archives of General Psychiatry, 40:1250-1254, 1983. Hannay, J.; Leli, D.; Falgout, J.; Katholi, C ; and Halsey, J. rCBF for middle-aged males and females during right-left discrimination. Cortex, 19:465-474. 1983. Hatazawa, J.; Brooks, R.A.; Di Chiro, G.; and Campbell, G. Global cerebral glucose utilization is independent of brain size: A PET Study. Journal of Computer Assisted Tomography. 11:571-576, 1987. Ingvar, D.H. "Hyperfrontal" distribution of the cerebral matter flow in resting wakefulness: On the functional anatomy of the conscious state. Acta Neurologica Scandinavica, 60:12-25, 1979. Kety, S.S., and Schmidt, C.F. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: Theory, procedures and normal values. Journal
of Clinical Investigation, 27:476-483, 1948. Mathew, R.J.; Wilson, W.H.; Tant, S.R.; Robinson, L.; and Prakash, R. Abnormal resting regional cerebral blood flow patterns and their correlates in schizophrenia. Archives of General Psychiatry, 45:542-549, 1988. Melamed, E.; Lavy, S.; Bentin, S.; Cooper, G.; and Rinot, Y. Reduction in regional cerebral blood flow during normal aging in man. Stroke, 11:31-35, 1980. Messerli, F.H.; Garavaglia, G.E.; Schmieder, R.E.; Sundgaard-Riise, K.; Nunez, B.D.; and Amodeo, C. Disparate cardiovascular findings in men and women with essential hypertension. Annals of Internal Medicine, 107:158-161, 1987. Obrist, W.D.; Thompson, H.K.; Wang, H.S.; and Wilkinson, W.E. Regional cerebral blood flow estimated by 133 xenon inhalation. Stroke, 6:245-256, 1975. Olesen, J.; Paulson, O.B.; and Lassen, N.A. Regional cerebral blood flow in man determined by the initial slope of the clearance of intra-arterially injected 133Xe. Stroke, 2:519-540, 1971. Ott, E.; Fazekas, F.; Bertha, G.; Valetitsch, H.; and Lechner, H. Theological determinants of cerebral blood flow. In: Hartmann, A., and Hoyer, S., eds. Cerebral Blood Flow and Metabolism Measurements. BerlinHeidelberg: Springer-Verlag, 1985. pp. 123-129. Risberg, J.; AH, Z.; Wilson, E.M.; Wills, E.L.; and Halsey, J.H. Regional cerebral blood flow by 133 xenon inhalation—Preliminary evaluation of an initial slope index in patients with unstable flow compartments. Stroke, 6:142-148, 1975. Rodriguez, G.; Warkentin, S.; Risberg, J.; and Rosadini, G. Sex differences in regional cerebral blood
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Xenon Xe 133 inhalation method. Archives of General Psychiatry, 40:258-263, 1983. Baxter, L.R.; Mazziotta, J.C., Jr.; Phelps, M.E.; Selin, C.E.; Guze, B.H.; and Fairbanks, L. Cerebral glucose metabolic rates in normal human females versus normal males. Psychiatry Research, 21:237-245, 1987.
253
254
flow. Journal of Cerebral Blood Flow
Warach, S.; Gur; R.C.; Gur, R.E.; Skolnick, B.E.; Obrist, W.D.; and Reivich, M. The reproducibility of the 133-xenon inhalation technique in resting studies: Task order and sex related effects in healthy young adults. Journal of Cerebral Blood Flow
and Metabolism, 7:702-708, 1987. Yoshii, E; Barker, W.W.; Chang, J.Y.; Loewenstein, D.; Apicella, A.; Smith, D.; Boothe, T.; Ginsberg,
Back Issues Available
M.D.; Pascal, S.; and Duara, R. Sensitivity of cerebral glucose metabolism to age, gender, brain volume, brain atrophy, and cerebrovascular
NS-14867 (Regional Brain Metabolism and Dopamine [D2] Receptors in Schizophrenia.)
risk factors. Journal of Cerebral Blood Flow and Metabolism, 8:654-661, 1988.
The Authors Acknowledgments This work was supported by National Institute of Mental Health grants 00586 (Research Scientist Development Award, Level II), MH-43880 (Mental Health Clinical Research Center in Schizophrenia), MH-42191 (A Neurobehavioral Study of Schizophrenia), and National Institutes of Health grant
Raquel E. Gur, M.D., Ph.D., is Professor of Psychiatry and Neurology, and Ruben C. Gur, Ph.D., is Professor of Psychology in Psychiatry, Brain Behavior Laboratory, Neuropsychiatry Program, and the Cerebrovascular Research Center, Departments of Psychiatry and Neurology, University of Pennsylvania, Philadelphia, PA.
Two back issues of the Schizophrenia Bulletin are still available to requesters: Schizophrenia Bulletin, Vol. 13, No. 2, 1987 (Assorted topics, including prognosis and phenomenology) Schizophrenia Bulletin, Vol. 13, No. 3, 1987 (Issue theme: High risk research) If any or both of these issues are missing from your collection, let us know, and we will send you a copy free of charge. Requests should be sent to the following address: Schizophrenia Research Branch National Institute of Mental Health Parklawn Bldg., Rm. 10C-06 5600 Fishers Lane Rockville, MD 20857
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
and Metabolism, 8:783-789, 1988. Shaw, T.G.; Mortel, K.F.; Meyer, J.S.; Rogers, R.L.; Hardenberg, J.; and Cutaia, M.M. Cerebral blood flow changes in benign aging and cerebrovascular disease. Neurology, 34:855-862, 1984.
SCHIZOPHRENIA BULLETIN
Gender Differences in Regional Cerebral Blood Flow
by Raquel E. Gur and Ruben C. Gur
Abstract
for measuring rCBF, then summarize the literature pertaining to gender differences, and finally discuss studies that examined gender differences in rCBF associated with schizophrenia. The
133
Xe Method
All current isotopic techniques for measuring cerebral metabolism and blood flow can be traced to the pioneering work of Kety and Schmidt (1948), who described a method for measuring whole-brain metabolism and blood flow. Their use of nitrous oxide and measurement of arterial-venous differences in concentration yielded accurate and reproducible data. However, this technique is not only limited to providing whole-brain values, but also is invasive, requiring catheterization of the carotid artery. Safe regional measurements of rCBF were first made possible by the introduction of the 133Xe clearance techniques. The highly diffusible 133Xe gas is administered either mixed in air for inhalation or in saline for intravenous infusion. Its clearance from the brain can be measured by stationary scintillation detectors. The rate of clearance enables quite accurate quantitation of rCBF in the fast-clearing gray matter compartment, as well as calculation of mean flow of gray and white matter. Initial applications used carotid injections (Olesen et al. 1971), which were invasive and only enabled measurements in one hemisphere at a time. In 1975, Obrist et al. (1975) and Risberg et al. (1975)
The application of techniques for measuring regional cerebral blood flow (rCBF) to the study of brain function provides the means to assess physiological concomitants of brain activity. In combination with task performance, which is introduced as a challenge, this research paradigm is the most direct avenue to investigate brain-behavior relationships. Gender is a major moderating variable in brain function, and hence it is not surprising that when sex differences in rCBF were examined, they were substantial. Since there are sex differences in psychopathology, as documented extensively in this issue of the Schizophrenia Bulletin, it is interesting to examine whether these may have substrates in regional brain physioReprint requests should be sent to Dr. logical activity reflected in rCBF. In R.E. Gur, University of Pennsylvania, this article we first present the Brain Behavior Laboratory, 205 Piersol 133 xenon (133Xe) inhalation method Bldg., Philadelphia, PA 19104.
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Gender differences have been noted in neurobehavioral studies. The "'xenon inhalation method for measuring regional cerebral blood flow (rCBF) can contribute to the understanding of the neural basis of gender differences in brain function. Few studies have examined gender differences in rCBF. In studies of normal subjects, women have higher rates of CBF than men, and this is related to age. Usually by the sixth decade men and women have similar flow rates. Fewer studies on rCBF in schizophrenia have examined sex differences. The pattern of higher flows for females maintains, but its correlates with gender differences in clinical as well as other parameters of brain function remain to be examined.
247
SCHIZOPHRENIA BULLETIN
248
duced that enables the placement of up to 254 detectors. The quantitative data can be displayed topographically (see figure 1). Note that rCBF is typically higher in the front of the brain. This "hyperfrontal" pattern has been observed routinely in normal subjects (Ingvar 1979). The main limitation of the technique is that it is optimal for measuring rCBF only on the brain surface near the skull, and hence it can be used to study primarily cortical brain regions.
Figure 1. Topographic display of regional CBF in a group of normal males (upper row) and females (lower row) during rest (column 1), a verbal analogies task (column 2), and a spatial line orientation task (column 3)
This method has been applied to many clinical populations, and normative data are extensive. In a challenge paradigm, subjects are engaged in a specific task during the period of measurement. We have used a repeated-measures design, where each participant undergoes three blood flow measurements, each lasting 15 minutes, in a single session. The tasks are presented in a counterbalanced order to control for the potential effect of factors such as novelty, anxiety, and fatigue. To measure hemispheric functioning, subjects are presented with a verbal task (analogies) and with a spatial task (line orientation), and rCBF is obtained during problem solving. Other tasks can be presented, depending on the hypotheses to be tested. Gender Differences in rCBF in Normal Subjects
Note the hyperfrontal pattern at rest, the higher cerebral blood flow (CBF) in females, and the increased CBF in the left for the verbal task and the right for the spatial task.
Despite the extensive literature on rCBF and on gender differences in brain function, only a few studies have examined gender differences in rCBF. We have measured rCBF in a sample of 62 young normals, 30 males and 32 females, with the cognitive activation paradigm described above. As can be seen in figure 2, blood flow rates were higher in females than in males (F = 15.55; df = 1,58; p < 0.001). Gender differences in the magnitude of 15 percent were evident for the initial slope (IS) index of gray matter flow as well as for all other indices. This difference, which existed for right-handers (n = 30) and left-handers (n = 32) at rest and during performance of both tasks, was significant for every detector. The effect did not diminish when factors which might influence rCBF
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
reported the 133Xe inhalation technique, and presented models for quantifying rCBF with this noninvasive procedure. The technique permits simultaneous measurements from both hemispheres, and the number of brain regions that can be measured depends on the number of detectors. Initial studies were performed with up to 16 detectors, 8 over each hemisphere, but there are now commercially available systems with 32 detectors and recently a system has been intro-
249
VOL. 16, NO. 2, 1990
Figure 2. Initial slope index of blood flow to the left (solid line) and right (dashed line) hemispheres in right- and left-handed males and females during 3 conditions1 Right-handers
Left-handers
o •o o o
X
80
•o
c
©
a o = c
7 0
I
_L R
V
S
R
V
S
R
V
S
Females (O). Males (D) Resting state (R) Verbal task (V). Spatial task (S) 'Reprinted, with permission, from Gur et al. (1982). Copyright © American Association for the Advancement of Science, 1982.
were considered: hemoglobin, diastolic and systolic blood pressure, and the partial pressure of CO2. In an extended sample (Gur et al. 1987b) of 55 right-handers, aged 18 to 72 years, subjects were divided into three age groups balanced for sex (< 20, 20-30, and > 30). As can be seen in figure 3, females had higher flows in all three groups, though the difference was most marked for the youngest group. A similar pattern of results was obtained in a subsequent study (Gur et al. 1988) where the effects of task difficulty on rCBF were examined
in relationship to anxiety and performance in 14 men and 12 women. Again, females had significantly higher rCBF. Shaw et al. (1984) examined CBF changes in benign aging in a sample of 130 normal subjects. While significantly higher gray matter flows were observed in women (« = 76) relative to men (n = 54) in the fourth to sixth decades, the gender difference was not significant after the sixth decade. A sample of 39 women was compared to 16 men by Davis et al. (1983), and the results reported were similar to those observed in the
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Total sample 90 r
studies above. Mean cerebral gray matter flow was higher in women in the second to fourth decades but not thereafter. More recently, Rodriguez et al. (1988) compared 38 men and 38 women who ranged in age from 18 to 72 years. An 11 percent increase in flow was evident in women across age groups with more symmetrical flows than seen in men. It should be noted that some studies reported no gender differences in CBF (Melamed et al. 1980; Hannay et al. 1983). The basis for higher flows in women is not clear. A number of factors might explain the gender differences. While the most obvious influence of blood pressure and p CO2 do not appear to affect the results obtained, other systemic factors might mediate. Shaw et al. (1984) suggested that low blood viscosity associated with menstruation might result in higher blood flow. CBF is affected by whole blood viscosity (Ott et al. 1985), and hemoglobin is correlated with oxygen-carrying capacity and inversely with CBF (Brown and Marshall 1985). However, Gur et al. (1982) could not account for the differences in CBF between males and females on the basis of hemoglobin. Furthermore, cerebral metabolism should not be affected by oxygen-carrying capacity, yet females have higher glucose metabolism (Baxter et al. 1987; Yoshii et al. 1988). It is possible the endocrine factors moderate the relationship with CBF and metabolism, and the effect of estrogen remains to be examined systematically. Other possible systemic factors that might contribute to the physiological differences in brain function are heart rate, pulse pressure, and cardiac index, which are higher in females than in males (Messerli et al. 1987). These will
250
Figure 3. Hemispheric cerebral blood flow for resting (R), verbal (V), and spatial (S) conditions for the 3 age groups1
lead to higher body blood flow, including brain, in women. Another potential explanation relates to differences in brain size between the genders (Buerger 1960). Thus, females have a higher rate of blood flow and metabolism, per 100 grams of brain tissue, to compensate for lower brain volume. This possibility was examined in a positron emission tomography study by Hatazawa et al. (1987), where women had a 9 percent increase in metabolism and 9 percent lower brain size, compared to men. A recent study from our laboratory suggests that the gender differences exist not only in absolute values of rCBF, but also in rCBF measures of habituation. Warach et al. (1987) examined the effects of repeated resting rCBF measurement in a sample of young men and women. For the whole sample, there was no significant difference between first and second resting measures, whether administered at the beginning of a session (before activation procedures were applied) or later on. Indeed, the reliability of rCBF measures with the 1MXe technique was exceedingly high, with correlations ranging from 0.86 to 0.97 for flow indices. However, there was a significant Order x Sex group interaction. Repeated initial studies showed reduced CBF from the first to the second resting measurement, but no reduction when the two resting measures were taken later in the series of studies (e.g., when the first two measures were obtained during task performance). The interaction with gender indicated that reduced CBF in serial measures was more pronounced in females. This finding is similar to effects reported for other neurophysiological measures of habituation, and it underscores the importance of
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Solid lines = left hemisphere. Dashed lines = right hemisphere. Triangles = men. Circles = women. 'Reprinted, with permission, from Gur et al. (1987a). Copyright © American Medical Association, 1987.
SCHIZOPHRENIA BULLETIN
251
VOL. 16, NO. 2, 1990
Gender Differences in rCBF in Schizophrenia As in normal controls, most rCBF studies in schizophrenia were conducted as resting flows, and gender differences were not examined. Using the activation paradigm described above, we have compared a sample of 7 men and 8 women with schizophrenia to 11 men and 14 women healthy controls. Patients were on neuroleptic medications during the time of study. The interaction of Diagnosis x Sex x Task was significant (F = 4.08; df = 2,72; p < 0.02). As can be seen in figure 4, women with schizophrenia had a different pattern of rCBF during task performance than all other groups. They showed little change in CBF during cognitive activation with the greatest increase for the verbal task, whereas the other groups showed increased flow for both tasks, with the greatest increase for the spatial task. Age, clinical subtypes, and severity of illness did not alter the pattern observed. In a subsequent study, patients (11 men, 8 women) were evaluated off neuroleptics and
Figure 4. Mean changes in regional cerebral blood flow for schizophrenic and matched control subjects divided by sex1 80
80
Men
ID O |
Women
75
75
70
70
65
65
o c CO
!s
0 — -O Schizophrenics Normal Controls I
I
R = resting state. V = solving verbal analogies. S = performing spatial task. 'Reprinted, with permission, from Gur et al. (1983). Copyright © American Medical Association, 1983.
compared to 11 men and 8 women control subjects. As can be seen in figure 5, gender is one of the factors that contributed to the abnormal pattern of rCBF in schizophrenia. Males with schizophrenia show higher left hemispheric flows in anterior brain regions both at rest and during the performance of the verbal task. Furthermore, unlike controls who for the spatial task had the highest flows, with the right hemisphere showing greater perfu-
sion than the left, patients had lower flows for the spatial task, relative to the verbal task, with no evidence of hemispheric specialization. Females with schizophrenia differed from control females both in anterior and posterior brain regions. Anteriorly, they had less increase for the spatial task, whereas posteriorly they showed higher left hemispheric flows for all three conditions, failing to demonstrate hemispheric specialization.
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
controlling for habituation effects on serial measurements of rCBF and metabolism. Considering gender differences neurobehaviorally, and the possible other explanations stated above, can lead to a series of studies that may elucidate the mechanisms underlying sex differences in brain function. These are testable hypotheses that can be addressed systematically. They can shed light not only on variability in normal brain function, but also in pathological conditions where gender differences have been noted.
252
SCHIZOPHRENIA BULLETIN
Figure 5. Hemispheric flows for resting (R), verbal (V), and spatial (S) conditions in anterior (precentral) and posterior (postcentrai) brain regions of schizophrenic and matched control subjects1
Conclusions
£ 60
Normal Schizophrenic I Left Hemisphere - I Right Hemisphere
55 R V S Anterior
R V S Posterior
R V S Anterior
R V S Posterior
'Reprinted, with permission, from Gur et al. (1985). Copyright © American Medical Association, 1985.
Ariel et al. (1983) obtained resting flows in patients (21 males, 8 females) and controls (14 males, 8 females) and reported that sex was not a factor contributing to the diagnostic group differences. Guenther et al. (1986) compared a sample of 16 patients with schizophrenia (10 males, 6 females) to 16 patients (6 males, 10 females) with endogenous depression and 8 (5 males, 3 females) controls. The authors state that the small number of subjects in each group did not permit exploring sex differences in detail, but comparison among male
and female subgroups did not indicate gender differences in the major findings of the study. Mathew et al. (1988) measured resting flows in 108 patients (60 males, 48 females) and 108 controls with the same gender distribution. Females, whether patients or controls, had higher CBF. These studies are quite preliminary. In addition to the potential factors that are likely to contribute to gender differences in CBF in normal subjects, other variables should be considered in the study of schizophrenia. These factors relate
Although gender differences in brain function have been examined neurobehaviorally, relatively few studies have focused on physiological measurements that might underlie these gender differences. Most studies that examined gender differences with the 133Xe inhalation method found that women had higher flows than men. These differences appeared to decline with aging. Many factors can potentially account for this observation. The research on schizophrenia is meager as far as the examination of gender differences in blood flow. It appears that female patients have higher flows than males, and further investigation of the pattern at activation is indicated. While efforts are devoted to the understanding of gender differences in normal brain function, studies in schizophrenia also need to pay attention to clinical variables where gender differences emerge. The tools are now available to relate clinical dimensions to neurobehavioral, neuroanatomical, and neurophysiological indices of brain function. This effort is likely to contribute to the understanding of the neurobiology of schizophrenia.
References Ariel, N.R.; Golden, C.J.; Berg, R. A.; Quaife, M.A.; Dirksen, J.W.; Forsell, T; Wilson, J.; and Graber, B. Regional cerebral blood flow in schizophrenics: Tests using the
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Women
Men
80
to differences in presentation and course of the disorder, and they require special attention in the experimental design and data analysis.
VOL. 16, NO. 2, 1990
Brown, M.M., and Marshall, J. Regulation of cerebral blood flow in response to changes in blood viscosity. Lancet, 1:604-609, 1985. Buerger, M. Altern und Krankeit als Problem der Biomorphose. Leipzig: Thieme, 1960. Davis, S.M.; Ackerman, R.H.; Correia, J.A.; Alpert, N.M.; Chang, ].; Buonanno, R.; Kelley, R.E.; Rosner, B.; and Taveras, J.M. Cerebral blood flow and cerebrovascular CO2 reactivity in stroke-age normal controls. Neurology, 33:391-399, 1983. Guenther, W.; Moser, E.; MuellerSpahn, R; von Oefele, K.; Buell, U.; and Hippius, H. Pathological cerebral blood flow during motor function in schizophrenic and endogenous depressed patients. Biological Psychiatry, 21:889-899, 1986. Gur, R.C.; Gur, R.E.; Obrist, W.D.; Hungerbuhler, J.P.; Younkin, D.; Rosen, A.D.; Skolnick, B.E.; and Reivich, M. Sex and handedness differences in cerebral blood flow during rest and cognitive activity. Science, 217:256-261, 1982. Gur, R.C.; Gur, R.E.; Obrist, W.D.; Skolnick, B.E.; and Reivich, M. Age and regional cerebral blood flow at rest and during cognitive activity. Archives of General Psychiatry, 44:617-621, 1987a. Gur, R.C.; Gur, R.E.; Resnick, S.M.; Skolnick, B.E.; Alavi, A.; and
Reivich, M. The effect of anxiety on cortical cerebral blood flow and metabolism. Journal of Cerebral Blood Flow and Metabolism, 7:173-177, 1987b. Gur, R.C.; Gur, R.E.; Skolnick, B.E.; Resnick, S.M.; Silver, F.L.; Chawluk, J.B.; Muenz, L.; Obrist, W.D.; and Reivich, M. Effects of task difficulty on regional cerebral blood flow: Relationships with anxiety and performance. Psychophysiology, 25:392-399, 1988. Gur, R.E.; Gur, R.C.; Skolnick, B.E.; Caroff, S.; Obrist, W.D.; Resnick, S.; and Reivich, M. Brain function in psychiatric disorders: III. Regional cerebral blood flow in unmedicated schizophrenics. Archives of General Psychiatry, 42:329-334, 1985. Gur, R.E.; Skolnick, B.E.; Gur, R.C.; Caroff, S.; Rieger, W.; Obrist, W.D; Younkin, D.; and Reivich, M. Brain function in psychiatric disorders: I. Regional cerebral blood flow in medicated schizophrenics. Archives of General Psychiatry, 40:1250-1254, 1983. Hannay, J.; Leli, D.; Falgout, J.; Katholi, C ; and Halsey, J. rCBF for middle-aged males and females during right-left discrimination. Cortex, 19:465-474. 1983. Hatazawa, J.; Brooks, R.A.; Di Chiro, G.; and Campbell, G. Global cerebral glucose utilization is independent of brain size: A PET Study. Journal of Computer Assisted Tomography. 11:571-576, 1987. Ingvar, D.H. "Hyperfrontal" distribution of the cerebral matter flow in resting wakefulness: On the functional anatomy of the conscious state. Acta Neurologica Scandinavica, 60:12-25, 1979. Kety, S.S., and Schmidt, C.F. The nitrous oxide method for the quantitative determination of cerebral blood flow in man: Theory, procedures and normal values. Journal
of Clinical Investigation, 27:476-483, 1948. Mathew, R.J.; Wilson, W.H.; Tant, S.R.; Robinson, L.; and Prakash, R. Abnormal resting regional cerebral blood flow patterns and their correlates in schizophrenia. Archives of General Psychiatry, 45:542-549, 1988. Melamed, E.; Lavy, S.; Bentin, S.; Cooper, G.; and Rinot, Y. Reduction in regional cerebral blood flow during normal aging in man. Stroke, 11:31-35, 1980. Messerli, F.H.; Garavaglia, G.E.; Schmieder, R.E.; Sundgaard-Riise, K.; Nunez, B.D.; and Amodeo, C. Disparate cardiovascular findings in men and women with essential hypertension. Annals of Internal Medicine, 107:158-161, 1987. Obrist, W.D.; Thompson, H.K.; Wang, H.S.; and Wilkinson, W.E. Regional cerebral blood flow estimated by 133 xenon inhalation. Stroke, 6:245-256, 1975. Olesen, J.; Paulson, O.B.; and Lassen, N.A. Regional cerebral blood flow in man determined by the initial slope of the clearance of intra-arterially injected 133Xe. Stroke, 2:519-540, 1971. Ott, E.; Fazekas, F.; Bertha, G.; Valetitsch, H.; and Lechner, H. Theological determinants of cerebral blood flow. In: Hartmann, A., and Hoyer, S., eds. Cerebral Blood Flow and Metabolism Measurements. BerlinHeidelberg: Springer-Verlag, 1985. pp. 123-129. Risberg, J.; AH, Z.; Wilson, E.M.; Wills, E.L.; and Halsey, J.H. Regional cerebral blood flow by 133 xenon inhalation—Preliminary evaluation of an initial slope index in patients with unstable flow compartments. Stroke, 6:142-148, 1975. Rodriguez, G.; Warkentin, S.; Risberg, J.; and Rosadini, G. Sex differences in regional cerebral blood
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
Xenon Xe 133 inhalation method. Archives of General Psychiatry, 40:258-263, 1983. Baxter, L.R.; Mazziotta, J.C., Jr.; Phelps, M.E.; Selin, C.E.; Guze, B.H.; and Fairbanks, L. Cerebral glucose metabolic rates in normal human females versus normal males. Psychiatry Research, 21:237-245, 1987.
253
254
flow. Journal of Cerebral Blood Flow
Warach, S.; Gur; R.C.; Gur, R.E.; Skolnick, B.E.; Obrist, W.D.; and Reivich, M. The reproducibility of the 133-xenon inhalation technique in resting studies: Task order and sex related effects in healthy young adults. Journal of Cerebral Blood Flow
and Metabolism, 7:702-708, 1987. Yoshii, E; Barker, W.W.; Chang, J.Y.; Loewenstein, D.; Apicella, A.; Smith, D.; Boothe, T.; Ginsberg,
Back Issues Available
M.D.; Pascal, S.; and Duara, R. Sensitivity of cerebral glucose metabolism to age, gender, brain volume, brain atrophy, and cerebrovascular
NS-14867 (Regional Brain Metabolism and Dopamine [D2] Receptors in Schizophrenia.)
risk factors. Journal of Cerebral Blood Flow and Metabolism, 8:654-661, 1988.
The Authors Acknowledgments This work was supported by National Institute of Mental Health grants 00586 (Research Scientist Development Award, Level II), MH-43880 (Mental Health Clinical Research Center in Schizophrenia), MH-42191 (A Neurobehavioral Study of Schizophrenia), and National Institutes of Health grant
Raquel E. Gur, M.D., Ph.D., is Professor of Psychiatry and Neurology, and Ruben C. Gur, Ph.D., is Professor of Psychology in Psychiatry, Brain Behavior Laboratory, Neuropsychiatry Program, and the Cerebrovascular Research Center, Departments of Psychiatry and Neurology, University of Pennsylvania, Philadelphia, PA.
Two back issues of the Schizophrenia Bulletin are still available to requesters: Schizophrenia Bulletin, Vol. 13, No. 2, 1987 (Assorted topics, including prognosis and phenomenology) Schizophrenia Bulletin, Vol. 13, No. 3, 1987 (Issue theme: High risk research) If any or both of these issues are missing from your collection, let us know, and we will send you a copy free of charge. Requests should be sent to the following address: Schizophrenia Research Branch National Institute of Mental Health Parklawn Bldg., Rm. 10C-06 5600 Fishers Lane Rockville, MD 20857
Downloaded from http://schizophreniabulletin.oxfordjournals.org/ at Universite de Sherbrooke on May 4, 2015
and Metabolism, 8:783-789, 1988. Shaw, T.G.; Mortel, K.F.; Meyer, J.S.; Rogers, R.L.; Hardenberg, J.; and Cutaia, M.M. Cerebral blood flow changes in benign aging and cerebrovascular disease. Neurology, 34:855-862, 1984.
SCHIZOPHRENIA BULLETIN
