Allergic tendencies are associated with larger gray matter volumes

Allergic tendencies are associated with important cognitive and physiological factors, such as intelligence and mathematical abilities. Allergies are widely prevalent, especially in modern life, and the reason for its association with important cognitive variables is an intriguing scientific question. However, despite the unique characteristics of cognitive correlates of allergy, the anatomical correlates of allergy remain unknown. The aim of this study was to identify the associations between regional gray matter volume (rGMV) and allergic tendencies in young adults. In a study cohort of 1,219 healthy, educated young adults, we identified a positive correlation between total allergic tendency and rGMV in large anatomical clusters that mainly encompassed the dorsal part of the cerebral neocortex, right anterior insula, and cerebellum. Furthermore,both mean rGMV of the entire part of these clusters and total allergenic tendency showed a significant positive correlation with spatial ability. These results suggest the link among allergic tendencies, larger rGMV, and the better spatial ability in healthy, educated young adults.


Supplemental Methods
Subjects. The present study, which is a part of an ongoing project to investigate the association between brain imaging, cognitive function, and aging, included 1219 healthy, right-handed individuals (703 men and 516 women) for whom relevant allergyrelated measures and structural imaging data were collected. The mean (± standard deviation, SD) age of the subjects was 20.7 ± 1.8 years (age range, 18-27 years). The following descriptions were mostly reproduced from another study of ours from the same project using the exactly same methods regarding these issues 1 . Psychological tests and MRI scans not described in this study were performed together with those described in this study. All subjects were university students, postgraduates, or university graduates of less than one year's standing. All subjects had normal vision and none had a history of neurological or psychiatric illness.
Handedness was evaluated using the Edinburgh Handedness Inventory 2 . We can say we used a score > 0 as the cutoff value. However, because the right-handed subjects were recruited through recruit informations of the bulletin board for the job and the email, almost all the left-handed subjects were removed in that process. Regardless, the previous VBM study with a large sample size failed to find any handedness effects on the regional morphology 3 ; thus, the effects of handedness on the regional morphology remain elusive.
Written informed consent was obtained from each subject. For nonadult subjects, written informed consent was obtained from their parents (guardians). This study was approved by the Ethics Committee of Tohoku University.
Subjects were instructed to get sufficient sleep, maintain their conditions, eat sufficient breakfast, and to consume their normal amounts of caffeinated foods and 4 drinks in the day of cognitive tests and MRI scans. In addition, subjects were instructed to avoid alcohol the night before the assessment.

Rationale for the use of self-reported measures to assess allergic tendencies
When assessing allergies, it is difficult to obtain doctors' diagnoses because it is unlikely that people who suffer from common allergies, such as hay fever, go to the hospital. Furthermore, to our knowledge, there are no established psychological measures to assess allergies in Japan.
Like other researches involving the association between allergy, asthma and cognition, the vast majority of relevant studies (the associations between hay fever, allergy, and cancer etc) have been performed with self-reported questionnaires 4 . Another study 5 developed and assessed a different type of questionnaire to measure allergic rhinitis.
Using a specialist's diagnosis of allergic rhinitis together with a positive skin prick test, they found 74% sensitivity and 83% specificity for their questionnaire. Our questionnaire is different; however, we have no reason to believe that the difference between the present questionnaire and a positive skin prick test affected the significant findings in such a way that they form false significant associations. segmentation process, default parameters were used, except that the Thorough Clean option was used to eliminate any odd voxel, affine regularization was performed with the International Consortium for Brain Mapping template for East Asian brains, and the sampling distance was set at 1 mm. We then proceeded to the diffeomorphic anatomical registration through exponentiated lie algebra (DARTEL) registration process implemented in SPM12. We used DARTEL import images of the 2 TPMs from the abovementioned new segmentation process. First, the template for the DARTEL procedures was created using imaging data from 800 participants (400 males and 400 females). The following methods were the same as in our previous study and descriptions were reproduced from our previous study 6 (These subjects were the first 400 male and 400 female subjects in this project). Next, using this existing template, the DARTEL procedures were performed for all of the subjects in the present study. In these procedures, default parameter settings were used. The resulting images were spatially normalized to the Montreal Neurological Institute (MNI) space to give images with 1.5 1.5  1.5 mm 3 voxels. In addition, we performed a volume change correction (modulation) by modulating each voxel with the Jacobian determinants derived from spatial normalization, which allowed us to determine regional differences in the absolute amount of brain tissue 7 . Subsequently, all images were smoothed by convolving them with an isotropic Gaussian kernel of 8 mm full width at half maximum (FWHM).

The effects of an interaction between sex and allergic tendency on cognitive function and rGMV
To investigate if the psychological and anatomical correlates of allergic tendency 6 differ between sexes, we performed an analysis of covariance (ANCOVA). Psychological analyses were performed in PASW Statistics 22 (SPSS Inc.). The dependent variables in these analyses were same as those used in the multiple regression analysis for investigation of the correlation with total allergic tendency across sexes. In the ANCOVA, sex was a fixed factor, and age, overall allergic tendency, and the interaction between sex and overall allergic tendency were added to the model.
To investigate the interaction effects of sex and individual overall allergic tendencies in a whole-brain analysis, we used a voxel-wise analysis of covariance (ANCOVA) in which sex difference was a group factor (using the full factorial option in SPM8). In this analysis, age, total intracranial volume, and overall allergic tendency were covariates, and age and overall allergic tendency were modeled to enable unique relationships with rGMV (using the interactions option in SPM8) for each sex. Total intracranial volume was modeled so that it has a common relationship with rGMV across sexes. The interaction effects between sex and overall allergic tendency were assessed using t-contrasts. A correction for multiple comparisons was performed with the same method used for the whole-brain multiple regression analysis.

The effects of an interaction between sex and allergic tendency on cognitive function and rGMV
There were no significant effects of interaction between sex and allergic tendency in the psychological or whole-brain analyses.

Limitations of this study
The present study had some limitations. Subjects in this study were young and healthy and consisted of mostly undergraduate or postgraduate students. This kind of limited sampling is a common hazard for studies using college students 8 . Thus, whether the present findings can be applied to the full population should be determined in future studies. However, for the purpose of this study, focusing on subjects with relatively high psychometric intelligence was important. This is because testosterone levels were previously described as relevant to allergic tendencies, and poor and high cognitive functioning are associated with higher testosterone levels [9][10][11] . Thus, studying a more educated, and perhaps more intelligent 12 , group was necessary for a simple and sensitive analysis. However, the average RAPM score, which was measured using a time limit of 30 min, was >28. This score is much >18, which was the score for the 50 percentile of a normative sample of Poland's 19 year olds published in 1991 13 [notably, the normative sample's general intelligence increased as time passed (Flynn effect) 13 ].
The higher psychometric intelligence in our present group may weaken the association between allergic tendency and psychometric intelligence observed in previous studies.
In addition, we did not measure circulating or prenatal testosterone levels. This was because of the limited research resources from multiple perspectives, and omission of this measurement did not hinder our fulfillment of the study's purpose. However, determining the association between testosterone levels and the variables used in the study, which were described in previous studies and outlined in the Introduction section, could enrich our study. 8

Supplemental table 1.
Anatomical classifications of the peaks and subpeaks of brain regions that exhibited a significant positive correlation between total allergic tendency and rGMV Temporal pole areas included all subregions in the areas of this atlas.

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Supplemental Table 2. Simple correlation coefficients and p-values for the associations between each allergy score and the significant allergy correlates in this study.