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A study of brain single-photon emission computed tomography in a sample of Egyptian autistic male versus female children: cross sectional (comparative study)

Omar, Manal; Hashem, Nivert Zaki; Ibrahim, Dina; El-Missiry, Marwa

Middle East Current Psychiatry: October 2012 - Volume 19 - Issue 4 - p 245–249
doi: 10.1097/01.XME.0000418719.34601.55
Original articles
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Background Autism is a neurodevelopmental disorder that affects boys more commonly than girls, with a range of heterogeneous presentations of clinical picture. There are several theories to explain these differences. These theories involve both genetic factors and phenotypic differences in how each sex manifests symptoms.

Aim This study aimed to examine and compare the functional neuroanatomical changes and differences between male and female children with autism using brain single-photon emission computed tomography.

Participants and methods Thirty children with autism spectrum disorder (10 girls and 20 boys) were assessed through brain imaging using 99mTc hexamethyl propylene amine oxime. The findings of males were compared with the findings of females using an independent Student’s t-test.

Results The frontal lobe was the most common area affected in both groups and showed high significant hypoperfusion, but the second common affected area differed; in males, it was the basal ganglia but in females it was the cerebellum.

Conclusion Functional techniques used in the assessment of this neurodevelopmental disorder are useful in explaining the difference in the presentations of autistic disorders among both males and females. Moreover, these findings may be helpful in the future for the management of these disorders.

aDepartment of Psychiatry, High Institute of Childhood Studies

bDepartment of Psychiatry, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Correspondence to Nivert Z. Hashem, Department of Psychiatry, Faculty of Medicine, Ain Shams University 11576 Cairo, EgyptTel: +201005171881; e-mail: nivertzaki@yahoo.com

Received October 17, 2011

Accepted February 1, 2012

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Background

Statistics on autism show that four times as many boys as girls are diagnosed with the disorder. There are several theories as to why autism appears to be more prevalent in boys than in girls. These theories involve both genetic factors and differences in how each sex manifests symptoms 1.

Autism, a developmental disorder that primarily affects communication and behavioral skills, is diagnosed four times more often in boys than in girls. Although professionals are not entirely sure why autism statistics show that the disorder appears to skew highly toward the male sex, there are some theories that attempt to explain the common phenomenon of autism in boys. One possibility is that autism has a genetic component that is more likely to affect the male brain. Some experts suggest that boys show symptoms and characteristics of autism in a more obvious manner than girls do, resulting in a disparity in the number of diagnoses made 2.

The autism-related characteristics that are most often associated with boys are aggression, hyperactivity, and social immaturity. Boys who are on the autism spectrum often show negative behaviors in an external manner while at school or at home, making the disorder easier for teachers and parents to identify and seek treatment for. Boys are much less likely than girls to mask their autistic traits by copying the social behaviors that are shown by neurotypical children. This theory suggests that autism may not in actuality occur more frequently in boys, but that girls are often underdiagnosed because of their tendency to internalize certain symptoms 3.

Brain single-photon emission computed tomography (SPECT) can be very useful in the evaluation of autism but, given the considerations mentioned above, it is not surprising that for all practical purposes, there is no typical pattern for it. However, because brain SPECT is able to identify areas of hyperperfusion and/or hypoperfusion (e.g. overactivity or underactivity), it can be useful to the neuropsychiatrist for optimizing the treatment strategy. As is the case in other child and adolescent neuropsychiatric disorders, treatment of the comorbidity goes a long way toward improving the quality of life of the patient and the family.

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Aim of the study

The aim of this research was to examine and compare the brain SPECT changes in a matched sample of Egyptian male and female children with autism, using 99mTc hexamethyl propylene amine oxime brain SPECT.

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Participants and methods

The study was approved by the Ethical Committee of the Institute of Psychiatry Ain Shams University and informed consent was obtained from all parents of the participants included. It was a comparative cross sectional study.

Thirty children with the autism spectrum disorder (10 girls and 20 boys), mean age 7.36±2.5 years, range from 3 to 12 years, were recruited from the outpatient psychiatric clinic of the Institute of Psychiatry, Ain Shams University. All the autistic children fulfilled the criteria for autistic disorder according to the ICD-10 diagnostic criteria for research.

Twenty-five children (83%) had ‘typical autism’, three children (10%) were diagnosed with ‘atypical autism’, and two (6%) were diagnosed with Rett’s syndrome. The majority of the children included were left handed (73%); the rest (27%) showed ambivalent handedness. An experienced pediatrician examined the children thoroughly to exclude those with a history of neurological diseases, significant medical diseases, known infections, metabolic, or chromosomal diseases.

Children were also assessed using the Adaptive Behaviour Scale (ABS) constructed by Nihira et al. 4 and translated into Arabic and validated by Farag and Ramzy 5. The scale is used to assess the adaptive skills of emotionally disturbed children.

The brain metabolism was assessed through brain imaging using 99mTc hexamethyl propylene amine oxime, a Sophy gamma camera; DSX rectangular was used with a computed system to control the acquisition parameters and carry out data processing functions. A parallel whole low-energy super high-resolution collimator was used. The data were acquired using ‘step and shot technique’; two methods were used for reading of SPECT, which was performed by senior specialized radiologists.

The analysis of SPECT was carried out using two techniques. The first was the visual technique, in which the number of affected areas represents the extent of cerebral hypoperfusion and the predominantly affected area. The second technique was the quantitative analysis technique: three transaxial slices were summated at three levels to represent the frontal level, the basal ganglia level, and the cerebellar level. Regions of interests were drawn on each summated frame to calculate counts in superior, inferior frontal parietal, temporal, occipital, basal ganglia, and cerebral regions on both right and left sides.

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Statistics

Data obtained were tabulated, processed in a personal computer, and analyzed using the statistical package for social science version 13 (SPSS Inc., Chicago, Illinois, USA). Independent student’s t-test was used to evaluate the statistical differences in regional cerebral blood flow (rCBF) between male and female children. We used Pearson’s correlation coefficient for the bivariate correlation procedure.

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Results

In both male and female groups, 13/20 (65.0%) and 9/10 (90.0%), respectively, showed frontal lobe hypoperfusion, but the second area showing hypoperfusion differed in both groups. In the male group, the basal ganglia was the second area that showed hypoperfusion 5/20 (25.0%), which was not present at all in the female group for any abnormality. In the female group, the cerebellum was the second area that showed hypoperfusion 5/10 (50.0%); even after the exclusion of the two cases of Rett’s syndrome who had definite cerebellar deficit, 3/8 (37%) female patients showed cerebellar hypoperfusion.

It was found that only 4/20 (20.0%) male patients showed cerebellar hypoperfusion; two of them were nonidentical twins, one had an eldest autistic sister who was included in the sample, and the fourth case had no sibs, but his mother had a history of abortion and prenatal complications (Tables 1 and 2).

Table 1

Table 1

Table 2

Table 2

On comparison of areas showing hypoperfusion in both hemispheres in the patient group, and among male and female groups, the left side of the brain was the most common side showing hypoperfusion in most regions of interest (Tables 3 and 4).

Table 3

Table 3

Table 4

Table 4

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Quantitative single-photon emission computed tomography findings

On comparing male and female groups, the bilateral superior frontal region showed high significant hypoperfusion in the female group, greater than the male group, in the mean brain count as shown in Table 5.

Table 5

Table 5

Comparison of male and female groups in the ABS showed a significantly lower profile in the female group in the motor milestones of development and language development. In contrast, a significantly higher profile was found in the male group in terms of stereotyped behavior and self-mutilation behavior as shown in Table 6.

Table 6

Table 6

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Discussion

A positive relationship between hypoperfusion areas and some representative autistic symptoms in children with childhood autism has been reported in various studies 6. Impairments in communication and social interaction were positively correlated to the left medial prefrontal cortex, whereas an obsessive desire for sameness was correlated positively to the right hippocampus and amygdala. The relationship between brain perfusion SPECT and autistic spectrum disorders (ASD) symptoms has been reported in many studies 6–12. Although frontal lobe hypoperfusion 8 or temporal hypoperfusion 9–11 has been reported in the literature, no consistent results on the relationship between the hypoperfusion area and autistic symptoms have been found in ASD.

In our study, in the male group, the frontal lobe was the most common site for hypoperfusion, followed by the basal ganglia. In the female group, the frontal lobe was the most common site for hypoperfusion, but followed by the cerebellum. On comparing the quantitative SPECT findings using the mean brain count/pixel, the superior frontal lobe was the only region showing significant hypoperfusion in the female group. These findings were in accordance with the findings of a study carried out by Ohnishi et al. 6, in which they found hypoperfusion involving all brain areas, especially the frontal lobe and cerebellum, and yet they did not discuss sex differences in their findings.

However, other SPECT studies carried out on autistic children such as in a study carried out by Sasaki et al.13, in all children who participated in the study, interictal SPECT showed some hypoperfusion areas within the prefrontal cortex, the medial frontal cortex, the anterior cingulated cortex, the medial parietal cortex, or the anterior temporal cortex (right, left, or both). According to many previous studies 6–12, these areas appear to be strongly correlated with the symptoms of autism. The left medial prefrontal cortex is reported to be strongly correlated to the ‘theory of mind’ area 14,15.

Another study carried out by Gupta and Ratnam 16 used a segmental quantitative SPECT study to assess the cerebral perfusion abnormalities in autistic children with mental retardation. The results showed lower count values (30–40) in autistic children in comparison with the control group (75–85), indicating a generalized hypoperfusion. The frontal and prefrontal regions showed the maximum hypoperfusion 16.

Among other studies that have considered the relevance of sex among autistic patients was a study carried out by Tepest et al. 17, who measured the size of the corpus callosum (CC) using MRI; there were no significant differences in the dependent variables [CC, CC subsegments, and total brain volume (TBV)]. With respect to sex, only TBV was significantly increased in males compared with females, resulting in a significantly decreased CC/TBV ratio in males. This finding, however, was independent of sex and can be fully attributed to brain size. These findings do not support the hypotheses of impaired CC in high-functioning autistic adults as a subgroup of patients with autism spectrum disorders, and the sexual dimorphism hypothesis of the CC 17.

The most recent imaging study considering sex differences in brain functional connectivity density was carried out by Tomasi and Volkow 18; they reported that MRI data from 336 women and 225 men showed a sex dimorphism in the functional organization of the brain. Consistently across five research sites, women had 14% higher local functional connectivity density and up to 5% higher gray matter density than men in cortical and subcortical regions. The negative power scaling of the local functional connectivity density was steeper for men than for women, indicating that the balance between strongly and weakly connected nodes in the brain is different across sexes. The more distributed organization of the male brain than that of the female brain could explain the sex differences in cognitive style and behaviors and in the prevalence of neuropsychiatric diseases (i.e. autism spectrum disorder) 18.

So does the etiology causing autism differ according to sex? Interpretation of the results was difficult as no other similar work has used neuroimaging to differentiate autistic patients’ results according to sex. Only the epidemiological studies have discussed sex differences in autistic patients, which showed that there was a predominance of males in the autistic population. Most studies have reported a ratio of around four males to one female, but in a description of an autistic population that had comparatively high intelligence, the ratio was 13 : 1 males to females; in contrast, in a population of low intelligence, the ratio was 1 : 1 (even after the exclusion of Rett’s syndrome). This indicates that the severity of the disorder was greater among girls despite disruptive disorders are known to affect girls less commonly and when occurs it is more severer in females 19; it has long been known that among diagnosed autistic individuals, females have lower IQ than males 20,21, and there is indirect evidence that girls with autism have more severe brain damage than boys 22.

The only study that has been carried out in order to analyze the sex differences in autistic symptomatology has yielded contrasting results, reporting no difference between males and females 23, but these preliminary findings should be interpreted with caution and need to be replicated by other groups before conclusions can be drawn 24.

Moreover, in a study carried out by Makkonen et al. 25 on serotonin and dopamine transporter binding in children with autism determined by SPECT, it was reported that although there are age-specific and sex-specific alterations in cerebral perfusion in children 4–15 years of age 26, according to van Dyck et al. 27 and Kuikka et al. 28, there is no effect of sex and only a slight effect of aging on serotonin transporter-binding capacity.

SPECT studies have also been carried out previously not only to measure cerebral perfusion among autistic children but also to prove an evidence for a lack of normal hemispheric asymmetry as that done by Chiron et al.29. In their study, brain functional imaging with 133Xe-SPECT was used to measure left/right asymmetry and absolute values of rCBF in 18 children with autism ranging in age from four to 17 years and 10 age-matched controls. All controls, but only 10 children with autism were right-handed. The left-to-right indices, both hemispheric and regional, were positive in controls, indicating higher left than right rCBF values, but were negative in patients with autism. This inversion was statistically significant for total hemispheres, sensorimotor, and language-related cortex, and could be attributed to a significant decrease in the left absolute rCBF values in these regions in patients with autism. The inversion was independent of handedness, sex, and age. These results confirm the existence of left-hemispheric dysfunction in childhood autism, especially in the cortical areas devoted to language and handedness, leading to anomalous hemispheric specialization 29.

Finally, in our study, the ABS showed a significantly lower profile in the female group in terms of the motor milestones of development and language development. In contrast, a significantly higher profile was found in the male group in terms of stereotyped behavior and self-mutilation behavior. A similar study carried out by Lemon et al. 30 examined sex differences in neurobehavioral functioning in boys and girls with ASD. It showed that females with ASD showed a significant increase in stopping time (indicating poorer inhibition). By contrast, no response inhibition impairments were evident among males with ASD. Females with ASD may have a different neurobehavioral profile, and therefore different clinical needs, when compared with males with ASD. Nevertheless, the current findings indicate the possibility of neuropsychological differences in ASD across sexes that would presumably be associated with different clinical presentations and outcomes 30.

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Conclusion

Autism is a developmental disorder that affects males four times more than females. Although the real pathology underlying this disorder is not yet well known, there are evidences indicating that there are brain neuropathology and functional disorders underlying this disorder. A trial to correlate this sex difference in the presentations of this disorder and SPECT findings has also found differences between males and females; hence, more neuroimaging studies are required to study these differences.

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Acknowledgements

The authors thank Prof. Dr Zeinab Bishry, Prof. Dr Mona Abdel Hady, and Ass. Prof. Ahmed El-Missiry.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

autism; sex; single-photon emission tomography

© 2012 Institute of Psychiatry, Ain Shams University