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Changes in regional cerebral blood flow in patients with anorexia nervosa detected through single photon emission tomography imaging
5"18
BIOL PSYCHIATRY 1993;34:578-580
Changes in Regional Cerebral, Blood Flow in Patients with Anorexia Nervosa Detected through Single Photon Emission Tomography Imaging Shin-ichi Nozoe, Tetsurou Naruo, Yoshiaki Nakabeppu, Yuji Soejima, Masayuki Nakajo, and Hiromitsu Tanaka
Key Words: Glutamate hypothesis, schizophrenia, strychnine-insensitive glycine binding site, N-methyl-D-asp~,rtate receptor, postmortem brain, radio-labeled receptor assay
Introduction Anorexia nervosa (AN) is a syndrome characterized by selfimposed starvation linked t.,:, a p~,3,ehepatbt,].-gic,q! ~i.~turb',.-.ee on a perceptual/conceptual level (Bruch 1962). Gartinkcl (1974) reported that patients with AN were more preoccupied with thoughts ot tood and more anxious when hungry than the controls. Researches on higher cerebral function in relation to eating behavior are consequently indispensable for studying the etiology of an. orexia nervosa, Recent progresses in radionuclear medicine have made it possible to use Positron Emission Tomography (PET) and Single Photon Emission Computed Tomogr'lphy (SPECT) for br'dn imaging (Ell ct al 1987), This has encouraged research on a variety of neurological and psychiatric diseases using measurements of in vivo metabolic activity and blood flow (Mathew and Wilson 1990). Because numerous studies have demonstrated a close correlation between neural activity and blood flow in the central nervous system, measurement of regional cerebral blood flow (rCBF) may reflect regional neural activity (Busija and Heistad 1984). The main hypothesis of this study is that when patients with
From the First Departmentof Internal Medicine (SN, TN, YS, HT), the DepaNment of Radiology (YN, MN), Faculty of Medicine, Kagoshima University, Kagoshima City. Japan. Address reprint t~luests to: Shin-ichi Nozoe, MD. i~irst Department of Internal Medicine, Faculty of Medicine, Kagoshima University, 8-35-I, Sakuragaoka, Kagoshima City, 890, Japan. Received October 3. 1992: revised July 15, 1993. © 1993 Society of Biological Psychiatry
AN are presented with a stimulus ("food"), the rCBF in certain cortical areas will increase, The present study was designed to measure the rCBF of subjects with and without food stimulus both before and after therapy.
Methods Seven women (age: 19,0 _+ 5.2, mean _+ SD) with AN who met the DSM-III-R criteria (American Psychiatry Association 1987), and five healthy female volunteers who were gender and age-matched controls participated in the present study after informed consent was obtained, X-ray computed tomography (XCT) scans revealed no mass lesion nor major structural change in the patients. Because of ethical reasons the volunteers were not exposed to XCT scans. All subjects were right-handed and had no abnormal neurological findings. Each patient was examined before and after therapy with an average interval of 70.7 _ 20.7 days. To minimize radiation exposure, the control subjects were examined only once. Carbon dioxide (CO.,) measurement obtained by taking an arterial blood sample was avoided because this procedure was deemed to increase anxiety levels, Every SPECT examination was conducted in conditions that minimized the arousal of anxiety among the test subjects. Ten rain after antecubital vein acquisition, while the subjects were kept in a resting state with their eyes closed, a dose of 15 mCi technetium-99m-hexamethylpropylene amine oxime (PAO) developed by Neirinckx (1987), a brain perfusion agent, was injected. The first raw counts were taken after a 5 min interval using the Siemens ZLC/75 dual head0006-3223/93/$06.00
Brief Reports
BIOLPSYCHIATRY
579
1993,34:57~]-580
ROTA camera with low-energy multiparallel hole collimators and stored in the computer. Just after the first scanning, the subjects were instructed to eat a piece of custard cake (96 kcal) within 3 rain, using their left hand and keeping their eyes closed. During this time another injection of 15 mCi PAO was added. Five rain later the second raw counts were taken. We reconstructed the tomographic slices without attenuation correction to produce a series of one pixel (6.5 mm) thick axial slices. The slices were parallel to the orbitocanthal-meatal line. Three slices were chosen from each brain scan and were identified as containing areas corresponding to the following cortical lobes by comparison to a brain atlas (Kretschmann and Weinrich 1986): slice ! comprised the cerebellum, slice 2 encompassed the inferior frontal, temporal, and occipital lobes, and slice 3 included the superior frontal and p~triet~ lobes. Rectangular regions of interest (ROls) of 25 pixels were placed on both central sides of the cerebellum in slice I, and in the cortex of the lobes in s;ices 2 and 3. ROls were not placed on the subeortical areas that had inadequate resolution. The cerebellar ROls were used to standardize the ROIs of slices 2 and 3 using the following ratio: Ratio (R') =
ROl~oum of each cortex mean cerebellum ROl~oum
kR' I +k+R'
Before therapy, the patients showed positive increases in the values of the percentage of change in all regions and in particular, the greatest increases on both sides of the inferior frontal cortex region, superior frontal cortex region, and occipital cortex region among the three groups (Table 1). On the left side of the inferior cortex region, Dunnett's test detected a significant difference from the controls [p < 0.05]. After therapy, the patients showed significantly high R~s, values compared to the control on both sides of temporal cortex regions. On the left side of temporal cortex region, analysis of variance (ANOVA) analysis detected significant differences among the three groups [F(2.165 = 4.13, p = 0.0036], which was confirmed by Dunnett's test [p < 0.05]. On the right side of temporal cortex region, the ANOVA as well as the Dunnett's test also detected significant differences [F(2,16) = 7.20, p = 0.0059 and p < 0.01]. However, the differences in R,,m8 and percentage of change values in any of the cortical regions relative to the controls were not statistically significant.
Discussion
The R' value was recomputed for flow-dependent back diffusion using the Lassen algorithm (Woods et al 1991): corrected Ratio (R) =
Results
k = 2.
This algorithm has been validated through PET (lnugami et al 1988). Because the image analysis method was modeled after the method of Fox and Raichle (1984) and Woods et al (1991), the following expression was used to measure the difference between the R~,t (corrected R at rest), and R~a,tng (corrected R at eating): percentage of change = R~,,m~ - R,~t x 100%. Rrfs!
A significant increase in response to food intake in percentage of change values on the left inferior frontal cortex was detected (Table 1). One et al (1984) reported that neurons in the dorsolateral prefrontal cortex of monkeys have multiple functions related to all phases of complex, learned feeding behavior. Thus, cu~nitive functions related to feeding may exert a great influence upon the rCBF of the frontal cortex. Because most of the patients in the present study who had not had therapy felt discomfort while eating the cakes, food intake might exert some influence on the emotional state and arousal level of the patients, although we performed no examination to measure physiological conditions in this study. Nauta (19715 identified the frontal lobe as the cortical region having the most intimate connection with the arousal system. Mathew et al (1985) found that a decrease in the frontal perfusion of cerebral blood
Table I. Comparison of R,~,t, R~,,Jnsand Percentage of Change of the Patients with Anorexia Ncrvosa and the Controls [Mean (SD)I
Region
Left/ right
Inf. frontal L e f t Right Sup. frontal Left Right Temporal Left Right Parietal Left Right Occipital Left Right
Controls
Before therapy
After therapy
R~.~,
R~.,,.~
% change
R~.
Rca.ng
% change
R~,
Reallng
% change
0.94 (0.08) 0.94 (0.12) 0.81(0.07) 0.82 (0.05) 0.81 (0.05) 0.79 (0.09) 0.82 (0.04) 0.85 (0.05) 0.87 (0.09) 0.83 (0.08)
0.92 (0.08) 0.93 (0.09) 0.80(0.10) 0.82 (0.10) 0.81 (0.06) 0.83 (0.10) 0.83 (0.08) 0.83 (0.07) 0.85 (0.09) 0.84 (0.11)
-2.48 (3.85) -0.28 (5.82) -I.78(10.28) 0.54 (6.88) -0.16 (5.42) 5.11 (4.61) 1,52 (9.01) -2.96 (5.475 - 1.96 (5.09) 0.45 (6.17)
0.86 (0.06) 0.88 (0.07) 0.79(0.05) 0.79 (0.04) 0.85 (0.06) 0.88 (0.06) 0.84 (0.02) 0.84 (0.06) 0.86 (0.07) 0.84 (0,08l
0.92 (0.07) 0.94 (0.09) 0.83(0.09) 0,85 (0.10) 0.89 (0.08) 0.91 (0.06) 0.84 (0.05) 0.86 (0,09) 0.91 (0.10) 0.90 (0.06)
7,34 (8.92)" 8.93 (17.44) 5.64(14.64) 6.87 (13.65) 498 (9.54) 3,50 (6.43) 0.19 (6.23) 1.89 (9.12) 5.64 (5.41) 7.77 (8.24)
0.93 (0,08) 0.91 (0.05) 0.88(0,10) 0.84 (0.10) 0.90 (0.06)" 0,94 (0.06~' 0.86 (0.07) 0.89 (0.07) 0,94 (0.07) 0.91 (0.10)
0.94 (0.10) 0.93 (0.07) 0.85(0,14) 0.85 (0,10) 0.93 (0.08) 0.96 (0.09) 0.90 (0.09) 0.90 (0.08) 0.94 (0.10) 0.91 (0,12)
1.65 (6,24) 2.83 (6,87) 1.89(9.05) 5.42 (5.64) 3.52 (9.83) 2.08 (8.78) 4.05 (8.55) 1.96 (11.06) 0.55 (8.20) 0.75 (5.26)
Up < 0.05. bp < 0.01 versus the controls by Dunnea's test.
580
BIOLPSYCHIATRY 1993;34:578-580
flow was associated with the reduction in arousal through tranquilization induced by nonsedating doses of diazepam. The present findings of rCBF may be associated with the arousal of the emotional state exerted by anorexia nervosa during the anorexic phase. Because we have no physiological measurement in this study, more research is needed to conclude that this arousal is
Brief Reports
associated with a specific emotional state such as anxiety, conflict, rage or panic. The physical change of the patients or the effect of receiving the same examination twice may contribute the post therapeutic significant increases of Rrca values on both sides of temporal cortex regions when compared to those of the controls.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Bmch H (1962): Perceptual and conceptual disturbances in anorexia nervosa. Psychosom Med 2:187-194. Busija DW, Heistad DD (1984): Factors involved in the physiological regulation of the cerebral circulation, Rev Physiol Biochem Pharmacol I01:162-196, Ell PJ, Jarrilt PH, Costa DC, Cullum ID, Lui D (1987): Functional imaging of the brain. Semi Nucl Med 17:214-229. Fox fir, Raichle ME (1984): Stimulus Rate Dependence of regional cerebral blood flow in human striae cortex, demonstrated by positron emission tomography. J Neurophysiol 51:1109-1120. Garfinkel PE ( 1974): Perception of hunger and satiety in anorexia nervosa. Psychol Med 4:309-315. Inugami A, Kanno 1, Uemura K, et al (1988): Linearization correction of ~mTc-labeled hexamethyl-propylene amine oxime (HM-PAO) image in terms of regional CBF distribution: comparison of CtS: inhalation steady-state method measured by positron emission tomography. J Cereb Blood Flow Metab 8:$52-$60. I I.
Kretschmann HJ, Weinrich W (1986): Neuroanatomie der Kranieillen Computertomographie. 1st Japanese ed. Tokyo: lgakuShoin. Mathew RJ, Wilson WH, Daniel IX3 (1985): The effect of nonsedating doses of diazepam on regional cerebral blood flow. Biol Psychiatry 20:1109-1116. Mathew RJ, Wilson WH (1990): Anxiety and cerebral blood flow. Am J Psychiatry 147:838-849, Nauta WJH (1971): The problem of the frontal lobe: A reinterpretation, J Psychiatry Res 8:167-187, Neirinckx RD, Canning LR, Piper IM, et al (1987): Technetium99m d, I-HMPAO: A new radiopharmaceutical for SPECT imaging of regional cerebral blood peffusion. J Nucl Med 28:191-202, Ono T, Nishino H, Fukuda M, Sasaki K, Nishijo H (1984): Single neuron activity in dorsolateral prefrontal cortex of monkey during operant behavior sustained by food reward. Brain Res 311:323-332. Woods SW, Hegeman IM, Zubal IG, et al (1991): Visual stim. ulation increases Technetium-99m-HMPAO distribution in human visual cortex. J Nucl Med 32:210-215.
BIOL PSYCHIATRY 1993;34:578-580
Changes in Regional Cerebral, Blood Flow in Patients with Anorexia Nervosa Detected through Single Photon Emission Tomography Imaging Shin-ichi Nozoe, Tetsurou Naruo, Yoshiaki Nakabeppu, Yuji Soejima, Masayuki Nakajo, and Hiromitsu Tanaka
Key Words: Glutamate hypothesis, schizophrenia, strychnine-insensitive glycine binding site, N-methyl-D-asp~,rtate receptor, postmortem brain, radio-labeled receptor assay
Introduction Anorexia nervosa (AN) is a syndrome characterized by selfimposed starvation linked t.,:, a p~,3,ehepatbt,].-gic,q! ~i.~turb',.-.ee on a perceptual/conceptual level (Bruch 1962). Gartinkcl (1974) reported that patients with AN were more preoccupied with thoughts ot tood and more anxious when hungry than the controls. Researches on higher cerebral function in relation to eating behavior are consequently indispensable for studying the etiology of an. orexia nervosa, Recent progresses in radionuclear medicine have made it possible to use Positron Emission Tomography (PET) and Single Photon Emission Computed Tomogr'lphy (SPECT) for br'dn imaging (Ell ct al 1987), This has encouraged research on a variety of neurological and psychiatric diseases using measurements of in vivo metabolic activity and blood flow (Mathew and Wilson 1990). Because numerous studies have demonstrated a close correlation between neural activity and blood flow in the central nervous system, measurement of regional cerebral blood flow (rCBF) may reflect regional neural activity (Busija and Heistad 1984). The main hypothesis of this study is that when patients with
From the First Departmentof Internal Medicine (SN, TN, YS, HT), the DepaNment of Radiology (YN, MN), Faculty of Medicine, Kagoshima University, Kagoshima City. Japan. Address reprint t~luests to: Shin-ichi Nozoe, MD. i~irst Department of Internal Medicine, Faculty of Medicine, Kagoshima University, 8-35-I, Sakuragaoka, Kagoshima City, 890, Japan. Received October 3. 1992: revised July 15, 1993. © 1993 Society of Biological Psychiatry
AN are presented with a stimulus ("food"), the rCBF in certain cortical areas will increase, The present study was designed to measure the rCBF of subjects with and without food stimulus both before and after therapy.
Methods Seven women (age: 19,0 _+ 5.2, mean _+ SD) with AN who met the DSM-III-R criteria (American Psychiatry Association 1987), and five healthy female volunteers who were gender and age-matched controls participated in the present study after informed consent was obtained, X-ray computed tomography (XCT) scans revealed no mass lesion nor major structural change in the patients. Because of ethical reasons the volunteers were not exposed to XCT scans. All subjects were right-handed and had no abnormal neurological findings. Each patient was examined before and after therapy with an average interval of 70.7 _ 20.7 days. To minimize radiation exposure, the control subjects were examined only once. Carbon dioxide (CO.,) measurement obtained by taking an arterial blood sample was avoided because this procedure was deemed to increase anxiety levels, Every SPECT examination was conducted in conditions that minimized the arousal of anxiety among the test subjects. Ten rain after antecubital vein acquisition, while the subjects were kept in a resting state with their eyes closed, a dose of 15 mCi technetium-99m-hexamethylpropylene amine oxime (PAO) developed by Neirinckx (1987), a brain perfusion agent, was injected. The first raw counts were taken after a 5 min interval using the Siemens ZLC/75 dual head0006-3223/93/$06.00
Brief Reports
BIOLPSYCHIATRY
579
1993,34:57~]-580
ROTA camera with low-energy multiparallel hole collimators and stored in the computer. Just after the first scanning, the subjects were instructed to eat a piece of custard cake (96 kcal) within 3 rain, using their left hand and keeping their eyes closed. During this time another injection of 15 mCi PAO was added. Five rain later the second raw counts were taken. We reconstructed the tomographic slices without attenuation correction to produce a series of one pixel (6.5 mm) thick axial slices. The slices were parallel to the orbitocanthal-meatal line. Three slices were chosen from each brain scan and were identified as containing areas corresponding to the following cortical lobes by comparison to a brain atlas (Kretschmann and Weinrich 1986): slice ! comprised the cerebellum, slice 2 encompassed the inferior frontal, temporal, and occipital lobes, and slice 3 included the superior frontal and p~triet~ lobes. Rectangular regions of interest (ROls) of 25 pixels were placed on both central sides of the cerebellum in slice I, and in the cortex of the lobes in s;ices 2 and 3. ROls were not placed on the subeortical areas that had inadequate resolution. The cerebellar ROls were used to standardize the ROIs of slices 2 and 3 using the following ratio: Ratio (R') =
ROl~oum of each cortex mean cerebellum ROl~oum
kR' I +k+R'
Before therapy, the patients showed positive increases in the values of the percentage of change in all regions and in particular, the greatest increases on both sides of the inferior frontal cortex region, superior frontal cortex region, and occipital cortex region among the three groups (Table 1). On the left side of the inferior cortex region, Dunnett's test detected a significant difference from the controls [p < 0.05]. After therapy, the patients showed significantly high R~s, values compared to the control on both sides of temporal cortex regions. On the left side of temporal cortex region, analysis of variance (ANOVA) analysis detected significant differences among the three groups [F(2.165 = 4.13, p = 0.0036], which was confirmed by Dunnett's test [p < 0.05]. On the right side of temporal cortex region, the ANOVA as well as the Dunnett's test also detected significant differences [F(2,16) = 7.20, p = 0.0059 and p < 0.01]. However, the differences in R,,m8 and percentage of change values in any of the cortical regions relative to the controls were not statistically significant.
Discussion
The R' value was recomputed for flow-dependent back diffusion using the Lassen algorithm (Woods et al 1991): corrected Ratio (R) =
Results
k = 2.
This algorithm has been validated through PET (lnugami et al 1988). Because the image analysis method was modeled after the method of Fox and Raichle (1984) and Woods et al (1991), the following expression was used to measure the difference between the R~,t (corrected R at rest), and R~a,tng (corrected R at eating): percentage of change = R~,,m~ - R,~t x 100%. Rrfs!
A significant increase in response to food intake in percentage of change values on the left inferior frontal cortex was detected (Table 1). One et al (1984) reported that neurons in the dorsolateral prefrontal cortex of monkeys have multiple functions related to all phases of complex, learned feeding behavior. Thus, cu~nitive functions related to feeding may exert a great influence upon the rCBF of the frontal cortex. Because most of the patients in the present study who had not had therapy felt discomfort while eating the cakes, food intake might exert some influence on the emotional state and arousal level of the patients, although we performed no examination to measure physiological conditions in this study. Nauta (19715 identified the frontal lobe as the cortical region having the most intimate connection with the arousal system. Mathew et al (1985) found that a decrease in the frontal perfusion of cerebral blood
Table I. Comparison of R,~,t, R~,,Jnsand Percentage of Change of the Patients with Anorexia Ncrvosa and the Controls [Mean (SD)I
Region
Left/ right
Inf. frontal L e f t Right Sup. frontal Left Right Temporal Left Right Parietal Left Right Occipital Left Right
Controls
Before therapy
After therapy
R~.~,
R~.,,.~
% change
R~.
Rca.ng
% change
R~,
Reallng
% change
0.94 (0.08) 0.94 (0.12) 0.81(0.07) 0.82 (0.05) 0.81 (0.05) 0.79 (0.09) 0.82 (0.04) 0.85 (0.05) 0.87 (0.09) 0.83 (0.08)
0.92 (0.08) 0.93 (0.09) 0.80(0.10) 0.82 (0.10) 0.81 (0.06) 0.83 (0.10) 0.83 (0.08) 0.83 (0.07) 0.85 (0.09) 0.84 (0.11)
-2.48 (3.85) -0.28 (5.82) -I.78(10.28) 0.54 (6.88) -0.16 (5.42) 5.11 (4.61) 1,52 (9.01) -2.96 (5.475 - 1.96 (5.09) 0.45 (6.17)
0.86 (0.06) 0.88 (0.07) 0.79(0.05) 0.79 (0.04) 0.85 (0.06) 0.88 (0.06) 0.84 (0.02) 0.84 (0.06) 0.86 (0.07) 0.84 (0,08l
0.92 (0.07) 0.94 (0.09) 0.83(0.09) 0,85 (0.10) 0.89 (0.08) 0.91 (0.06) 0.84 (0.05) 0.86 (0,09) 0.91 (0.10) 0.90 (0.06)
7,34 (8.92)" 8.93 (17.44) 5.64(14.64) 6.87 (13.65) 498 (9.54) 3,50 (6.43) 0.19 (6.23) 1.89 (9.12) 5.64 (5.41) 7.77 (8.24)
0.93 (0,08) 0.91 (0.05) 0.88(0,10) 0.84 (0.10) 0.90 (0.06)" 0,94 (0.06~' 0.86 (0.07) 0.89 (0.07) 0,94 (0.07) 0.91 (0.10)
0.94 (0.10) 0.93 (0.07) 0.85(0,14) 0.85 (0,10) 0.93 (0.08) 0.96 (0.09) 0.90 (0.09) 0.90 (0.08) 0.94 (0.10) 0.91 (0,12)
1.65 (6,24) 2.83 (6,87) 1.89(9.05) 5.42 (5.64) 3.52 (9.83) 2.08 (8.78) 4.05 (8.55) 1.96 (11.06) 0.55 (8.20) 0.75 (5.26)
Up < 0.05. bp < 0.01 versus the controls by Dunnea's test.
580
BIOLPSYCHIATRY 1993;34:578-580
flow was associated with the reduction in arousal through tranquilization induced by nonsedating doses of diazepam. The present findings of rCBF may be associated with the arousal of the emotional state exerted by anorexia nervosa during the anorexic phase. Because we have no physiological measurement in this study, more research is needed to conclude that this arousal is
Brief Reports
associated with a specific emotional state such as anxiety, conflict, rage or panic. The physical change of the patients or the effect of receiving the same examination twice may contribute the post therapeutic significant increases of Rrca values on both sides of temporal cortex regions when compared to those of the controls.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Bmch H (1962): Perceptual and conceptual disturbances in anorexia nervosa. Psychosom Med 2:187-194. Busija DW, Heistad DD (1984): Factors involved in the physiological regulation of the cerebral circulation, Rev Physiol Biochem Pharmacol I01:162-196, Ell PJ, Jarrilt PH, Costa DC, Cullum ID, Lui D (1987): Functional imaging of the brain. Semi Nucl Med 17:214-229. Fox fir, Raichle ME (1984): Stimulus Rate Dependence of regional cerebral blood flow in human striae cortex, demonstrated by positron emission tomography. J Neurophysiol 51:1109-1120. Garfinkel PE ( 1974): Perception of hunger and satiety in anorexia nervosa. Psychol Med 4:309-315. Inugami A, Kanno 1, Uemura K, et al (1988): Linearization correction of ~mTc-labeled hexamethyl-propylene amine oxime (HM-PAO) image in terms of regional CBF distribution: comparison of CtS: inhalation steady-state method measured by positron emission tomography. J Cereb Blood Flow Metab 8:$52-$60. I I.
Kretschmann HJ, Weinrich W (1986): Neuroanatomie der Kranieillen Computertomographie. 1st Japanese ed. Tokyo: lgakuShoin. Mathew RJ, Wilson WH, Daniel IX3 (1985): The effect of nonsedating doses of diazepam on regional cerebral blood flow. Biol Psychiatry 20:1109-1116. Mathew RJ, Wilson WH (1990): Anxiety and cerebral blood flow. Am J Psychiatry 147:838-849, Nauta WJH (1971): The problem of the frontal lobe: A reinterpretation, J Psychiatry Res 8:167-187, Neirinckx RD, Canning LR, Piper IM, et al (1987): Technetium99m d, I-HMPAO: A new radiopharmaceutical for SPECT imaging of regional cerebral blood peffusion. J Nucl Med 28:191-202, Ono T, Nishino H, Fukuda M, Sasaki K, Nishijo H (1984): Single neuron activity in dorsolateral prefrontal cortex of monkey during operant behavior sustained by food reward. Brain Res 311:323-332. Woods SW, Hegeman IM, Zubal IG, et al (1991): Visual stim. ulation increases Technetium-99m-HMPAO distribution in human visual cortex. J Nucl Med 32:210-215.