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Keywords:

  • 3D-SSP;
  • anorexia nervosa;
  • posterior cingulate gyrus;
  • SPECT;
  • subcallosal gyrus

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Aims:  Anorexia nervosa (AN) is subdivided into the restricting type (AN-R) and the binge-eating/purging type (AN-BP), but differences in cerebral blood flow between patients with these types of AN and healthy controls have not been investigated.

Methods:  The present study was designed to elucidate any such differences using resting single photon emission computed tomography (SPECT) studies to compare the differences in cerebral perfusion among both types of AN and a healthy control group. Resting regional cerebral blood flow was assessed using SPECT with technetium-99m hexamethylpropyleneamine oxime in 13 female AN-R patients, 13 female AN-BP patients, and 10 healthy women as controls with 3-D stereotactic surface projections.

Results:  The analytic program of the SPECT images showed bilateral decreased perfusion of the subcallosal gyrus (SCG), midbrain and posterior cingulate gyrus (PCG) in both AN-R and AN-BP patients, as compared with the controls. There were no clear differences between the AN-R and AN-BP groups. There were no significant differences in cerebral blood flow between patients with AN-R and AN-BP.

Conclusions:  Abnormalities of the neuronal circuits containing the SCG, midbrain and PCG are possibly relevant to trait-related AN.

ANOREXIA NERVOSA (AN) is characterized by refusal to maintain bodyweight at or above a minimally normal weight for age and height; intense fear of gaining weight or becoming fat, even though underweight; disturbance in the way in which one's bodyweight or shape is experienced; undue influence of bodyweight or shape on self-evaluation, or denial of the seriousness of the current low bodyweight; and amenorrhea in postmenarcheal women. AN is further classified into two subtypes, that is, the restricting subtype (AN-R), in which the person has not regularly engaged in binge-eating or purging behavior, and the binge eating/purging subtype (AN-BP), in which the person has regularly engaged in binge-eating or purging behavior.1

Thus, there are some common or different clinical symptoms between AN-R and AN-BP patients. Several biological studies, such as neuroendocrine study,2–4 an event-related potentials study on P300,5,6 and a genetic study,7–9 have investigated the differences between AN-R and AN-BP. The understanding of the biophysiological differences between AN-R and AN-BP remains, however, unclear.

Neuroimaging studies have also been conducted to investigate brain functions in AN. Functional neuroimaging studies are among the most useful of methods to clarify the psychophysiological aspects of AN. To date, resting single photon emission computed tomography (SPECT) studies using voxel-based analysis have been performed.10,11 They have found a reduction of the regional cerebral blood flow (rCBF) in the brain cortex of AN patients before weight gain. To the best of our knowledge, only one resting SPECT study has been conducted to compare AN-R with AN-BP patients and control subjects,12 which demonstrated bilateral reduction of the rCBF in the anterior cingulate gyrus (ACG) in AN-R, but not in AN-BP patients.

Brain structural studies using computed tomography (CT) and magnetic resonance imaging (MRI) have generally found evidence of brain atrophy, so-called pseudo atrophy, in AN.13 Brain atrophy often affects the interpretation of SPECT images and causes measurement errors. Recently, however, analysis based on the development of 3-D stereotactic surface projections (3D-SSP) has been less influenced by brain atrophy,14,15 and accurate measurements of the rCBF in the brain cortex can be conducted even in patients with brain atrophy. Therefore, we used 3D-SSP for the analysis of SPECT images.

The primary aim of the present study was to investigate the differences in rCBF between AN patients and control subjects, and then to investigate the differences in rCBF between AN-R and AN-BP patients, by analysis of SPECT images using 3D-SSP.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Subjects

Thirteen women with AN-R and 13 women with AN-BP, all of whom met the DSM- IV criteria for the diagnosis of AN and without any diagnosed comorbid psychiatric disorders (e.g. depression, obsessive-compulsive disorder, borderline personality disorder),1 were recruited for the present study from among the inpatients of the Hiroshima Prefectural Hospital. We defined AN-R patients as never having had any history of binge eating/purging episodes; patients with early onset as defined by Lask and Bryant-Waugh16,17 were excluded from the analysis because the outcome in these cases has been shown to be different from that in core adolescent-onset cases. All AN-BP patients started as AN-R, and sometimes they swung between AN-R and AN-BP. We used this sample size in the present study because a sample size of almost the same number was fixed in previous studies using 3D-SSP analysis18 and resting SPECT studies of AN,12,19 and the agreed appropriate sample size is 10–20 subjects in positron emission tomography (PET) human studies using paired subtraction comparisons with blood flow differences.20 A minimum of two skilled psychiatrists established the diagnosis in all the study subjects according to the DSM-IV criteria.1 None of the patients had any abnormal findings on neurological examination or medical history of any organic brain disorder. Several patient participants were receiving pharmacotherapy. Seven of the patients took trazodone (50–150 mg/day) as the main pharmacotherapy, four of them took fluvoxamine (75–100 mg/day), and three of them took sulpiride (150–300 mg/day). They were also undergoing cognitive behavior therapy, and a combination of both. Ten healthy volunteers (the control group) served as age- and sex-matched controls, after being screened for abnormal eating habits and neurological or psychiatric disease.

After a full explanation of the procedures, written informed consent for participation in the study was obtained from all the subjects, and were also obtained from the parents of those subjects younger than 20. The study was conducted according to the regulations of the Institutional Review Board of Hiroshima Prefectural Hospital. The SPECT imaging was performed with the subjects in a stable psychological state such as pathological feeding behavior, anxiety, depressive mood and obsessive behavior as compared with their psychological state at admission, and the mean ± SD period was 18.2 ± 15.4 days after admission.

Statistical analysis of clinical and physiological background was performed using analysis of variance (anova).

Imaging technique

Measurement of the rCBF was conducted with high-resolution SPECT using technetium-99m hexamethylpropyleneamine oxime (HMPAO). The SPECT was performed with a triple-head rotating camera (Toshiba GCA9300, Toshiba, Yokyo, Japan) under standard resting conditions (eyes closed) in all the study subjects.

The image acquisition was started 30 min after i.v. administration of 740 MBq of 99mTc HMPAO, and lasted >30 min. The distance of the collimators from the center of rotation was kept constant at 13.2 cm. A low-energy, high-resolution collimator and a 128 × 128 acquisition matrix were used for the data acquisition. Images were reconstructed with a Butterworth filter (cut-off frequency 0.17 cycle/pixel order 8; Toshiba, Yokyo, Japan), which yielded a reconstructed image resolution of approximately 13 mm at the center of rotation. The pixel size in the reconstructed images was 3.44 mm. Attenuation was corrected according to Chang's technique using an absorption coefficient of 0.15/cm.21 The system resolution of this SPECT was 8.0 mm at full width half maximum.

Image analysis

To measure the relative decrease of the uptake of HMPAO, we used 3D-SSP, which is a semiquantitative analytic approach originally developed by Minoshima et al.22

3D-SSP analysis

Each image set was realigned to the bicommissure stereotactic coordinate system.23 The differences in the brain size among individuals were eliminated by linear scaling, and regional anatomical differences were minimized using a non-linear warping technique.24 As a result, each brain was standardized anatomically to match a standard atlas brain, while preserving regional perfusion activity. Subsequently, the maximum cortical activity was extracted to adjacent predefined surface pixels on a pixel-by-pixel basis using the 3D-SSP technique. In this approach, the outer brain contour covering the entire lateral and medial hemispheres is predefined on a standard atlas. For each predefined contour pixel, a search for the peak cortical pixel is conducted in a standardized individual's image set on a predefined line perpendicular to the standard atlas contour, with a search depth of 6 pixels. The search depth was equal to 13.5 mm, which approximately covers the peak gray matter activity on the SPECT image sets. The peak cortical pixel value was assigned to the corresponding surface pixel (surface projection), and the search was repeated for all the predefined contour pixels. The extracted 3D-SSP data could be viewed from the superior, inferior, right, left, anterior, posterior and two medial aspects of the brain. Thus, 3D-SSP can transform a SPECT image of a subject to a coordinate of Talairach (anatomical standardization), and the x, y, and z coordinates of the 3D-SSP Z-score image correctly correspond to the coordinates of Talairach.23,24 Data sets were normalized to the mean thalamic activity, and between-group comparisons were performed using the t-test on a pixel-by-pixel basis. To demonstrate regional patterns of alterations of the rCBF, two sample t-test values were calculated on a pixel-by-pixel basis between normal controls and AN-R patients, and between normal controls and AN-BP patients, and the values were then transformed to Z-values by a probability integral transformation. We chose the Z = 3 as the cut-off for significance based on previous reports,25 because a two-tailed P < 0.005 is equivalent to Z-score >2.81, and a two-tailed P < 0.001 is equivalent to a Z-score >3.29, taking a false positive reaction into account.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Demographic data

The characteristics of the four groups of subjects are presented in Table 1. Significant differences between AN-All (AN-R + AN-BP) and controls, between AN-R patients and controls, between AN-BP patients and controls, and between AN-R and AN-BP groups were indicated. There were no significant differences in the mean age among the four groups; and body mass index (BMI), the duration of the illness, onset age, and the duration of the current episode did not differ significantly between the AN-R and the AN-BP groups.

Table 1.  Clinical and physiological characteristics (mean ± SD)
 Age (years)BMI (kg/m2)Duration of illness (months)Onset age (years)Duration of current episode (months)Main pharmacotherapy (medication/n)
  • Significantly different from the control group (P < 0.05), anova.

  • AN-All, total anorexia nervosa group; AN-BP, bingeing/purging subtype of anorexia nervosa; AN-R, restricting subtype of anorexia nervosa; Flu, Fluvoxamine; Sul, Sulpiride; Tra, Trazodone.

Control (n = 10)20.6 ± 1.719.7 ± 1.8(–)(–)(–)(–)
AN-All (n = 26)22.2 ± 3.913.5 ± 1.332.0 ± 22.419.7 ± 4.37.0 ± 6.1Tra/7, Flu/4, Sul/3
AN-R (n = 13)22.2 ± 3.613.8 ± 1.530.3 ± 23.719.6 ± 4.64.5 ± 5.3Tra/3, Sul/2
AN-BP (n = 13)22.3 ± 4.413.4 ± 1.233.8 ± 21.919.7 ± 4.28.7 ± 7.1Tra/4, Flu/4, Sul/1

Neuroimaging data

Not only the thalamus but also other regions such as the whole brain or the cerebellum or the pons can be used for normalization in 3D-SSP. When we selected the whole brain or the cerebellum or the pons as control for the normalization, the same results were obtained as the thalamus.

As compared with the control group, the AN-All groups showed decreased perfusion in the region of the bilateral subcallosal gyrus (SCG), posterior cingulate gyrus (PCG), corpus callosum, midbrain, and pons (Table 2; Fig. 1). There were no areas showing increased perfusion.

Table 2.  Relative perfusion reduction areas compared to control (Z score >3)
 RegionCoordinateMax Z score
XYZ
  1. AN-All, total anorexia nervosa group; AN-BP, bingeing/purging subtype of anorexia nervosa; AN-R, restricting subtype of anorexia nervosa.

AN-All
RightSubcallosal Gyrus−15−133.663
Posterior cingulate gyrus−1−13273.546
Corpus Callosum−1−13−253.813
Midbrain−1−35−43.201
Pons−11−203.543
LeftSubcallosal Gyrus13−164.422
Posterior cingulate gyrus113−273.121
Corpus Callosum1−17233.691
Midbrain1−28−73.513
Pons11−204.115
AN-R
RightSubcallosal Gyrus15−163.997
Posterior cingulate gyrus1−4293.060
Corpus Callosum1−37114.330
Midbrain1−35−43.430
LeftSubcallosal Gyrus−13−164.814
Posterior cingulate gyrus−1−33183.071
Paracentral lobule−1−19453.796
Midbrain−1−28−43.099
AN-BP
RightAnterior cingulate gyrus128−73.373
Subcallosal Gyrus13−184.463
Posterior cingulate gyrus1−5853.023
Midbrain−1−35−43.201
Pons−11−203.543
LeftSubcallosal Gyrus−13−163.868
Posterior cingulate gyrus−1−49233.409
Cerebellum−1−42−294.120
Midbrain−1−28−43.099
image

Figure 1. Z-score images of relative perfusion reduction areas in the anorexia nervosa restricting- or bingeing/purging-type patients (AN-All) compared to healthy controls (Z score >3). ANT, anterior; INF, inferior; LAT, lateral; LT, left; MED, medial; POST, posterior; RT, right; SUP, superior.

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As compared with the control group, the AN-R groups had decreased perfusion in the region of the bilateral SCG, midbrain, PCG, left paracentral lobule, and right corpus callosum (Table 2; Fig. 2). There were no areas showing increased perfusion.

image

Figure 2. Z-score images of relative perfusion reduction areas in patients with restricting subtype of anorexia nervosa (AN-R) and the bingeing/purging subtype (AN-BP) when compared to healthy controls (Z score >3). ANT, anterior; INF, inferior; LAT, lateral; LT, left; MED, medial; POST, posterior; RT, right; SUP, superior.

Download figure to PowerPoint

As compared with the control group, the AN-BP groups had decreased perfusion in the region of the bilateral SCG, midbrain and PCG, right ACG and pons, and left cerebellum (Table 2; Fig. 2). No areas showed increased perfusion.

Comparison between the AN-R and AN-BP groups found no significant differences in the rCBF between the two groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

In the present study, decreased perfusion in the bilateral SCG, PCG and midbrain was found in the AN patients (both AN-R and AN-BP) as compared with controls, but there was no difference between the two AN subtypes.

In a recent study, increases of rCBF were shown in the PCG following treatment of AN patients.10 Another study showed decreases of rCBF in the frontal lobe, including the PCG, in AN-R patients before treatment compared with controls.11 A previous PET study also showed decreases in regional cerebral metabolic rate of glucose in the PCG in AN patients compared with controls.26 The present findings that rCBF in the PCG decreased in AN patients compared with controls was in agreement with those studies. Several bodies of evidence have shown that the senses of taste and smell, and different foods and flavors activated specific regions such as the PCG, SCG, ACG, orbitofrontal cortex and amygdala, and these regions might be implicated in the modulation of the reward value of a sensory stimulus such as the taste of food.27–30 The decreased perfusion in the PCG might therefore be partially related to the pathophysiology of AN.

In contrast, there have been no studies on the changed rCBF in the SCG in AN subjects. PET studies of the 5-HT2A receptor showed an abnormality in SCG in AN patients, and this abnormality was shown in subjects who had recovered from both the restricting type recovered-AN (R-AN) (R-AN-R) and binge eating/purging type R-AN (R-AN-BP).31,32 In eating disorder patients the amygdala was shown to be activated by unpleasant stimuli, such as the patients' own body images and high-calorie foods.33,34 Deactivation of the SCG might result in failure of the function of the amygdala in reacting to unpleasant stimuli, because the SCG has interconnections with the amygdala.35 The SCG might be a region that plays a very important role in the psychopathology of AN.

Previous resting SPECT studies found decreased perfusion in the ACG in AN patients.12,19 In the present study, decreases of rCBF were observed in the SCG but not the ACG. Moreover, only one study has demonstrated that a bilateral decrease of the rCBF in the ACG is observed only in AN-R and not AN-BP patients in resting SPECT.12 Although the function of the ACG and SCG in AN is still unknown, the ACG (Broadmann area 24) and SCG (Broadmann area 25) play a common role involved in emotional response and are activated by sensory stimuli such as the taste of food.29,36 Thus, decreased rCBF in the SCG might be compensatory for changes in the ACG. Further studies are needed to address this issue. Another plausible explanation might be the differences in the analytic methods. We used 3D-SSP for analyzing the SPECT images, whereas others used statistical parametric mapping (SPM). However, further study using both methods would be needed to draw a definitive conclusion. As the third possibility, the absence of any significant differences in the duration of illness and the onset age between AN-R and AN-BP patients might explain the differences between the present results and the results of other studies. Further functional neuroimaging studies in AN subjects with detailed clinical background data will be essential to investigate the differences between AN-R and AN-BP subjects.

The present resting SPECT study found no significant differences in rCBF/activity between AN-R and AN-BP patients. The brain alternations were shared by the AN-R and the AN-BP patients. In other words, the present results might represent the common abnormalities between patients suffering from AN-R and AN-BP. In the clinical setting, AN-BP patients usually start the same way as AN-R patients, and frequently swing between the restricting type and bulimic/purging type of the disease.37 Eddy et al. stated that AN-R represents a phase in the course of AN rather than a distinct subtype.38

The present study also had the following limitations: although the diagnosis in the subjects was established by a minimum of two skilled psychiatrists, a structured clinical interview was not used in all of the subjects, nor was the severity of the AN or deficit in the physical status assessed in the subjects. Because of the limitation of the analytic program, 3D-SSP was unable to analyze the correlation between rCBF and clinical factors such as BMI, age, duration current episode of illness, onset age and duration of the current episode. It has been reported that changes in rCBF have been associated with interoceptive awareness in the recovery process from AN.10 In the present study we did not apply psychological assessments such as the eating disorder inventory. Some of the patient participants were taking mainly antidepressants. Numerous studies have demonstrated that administration of antidepressants did not decrease the cerebral blood flow.39,40 The tracer used in the study was HMPAO. The tracer has some quantification-related disadvantages compared with other tracers such as N-isopropyl-p-[123I] iodoamphetamine and 99mTc-ethyl-cistainate dimer. Last, we did not measure the extent of any of the subjects' brain atrophy using CT or MRI.

In conclusion, analysis of the resting SPECT images found no significant differences between patients with AN-R and AN-BP. Abnormalities of the neuronal circuits containing the SCG, midbrain and PCG are possibly relevant to the trait-related AN.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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