Resting cerebral blood flow alterations specific to the comitant exophoria patients revealed by arterial spin labeling perfusion magnetic resonance imaging

Accepted Manuscript Resting cerebral blood flow alterations specific to the comitant exophoria patients revealed by arterial spin labeling perfusion magnetic resonance imaging

Xin Huang, Sheng Zhou, Ting Su, Lei Ye, Pei-Wen Zhu, WenQing Shi, You-Lan Min, Qing Yuan, Qi-Chen Yang, Fu-Qing Zhou, Yi Shao PII: DOI: Reference:

S0026-2862(18)30109-2 doi:10.1016/j.mvr.2018.06.007 YMVRE 3807

To appear in:

Microvascular Research

Received date: Revised date: Accepted date:

3 June 2018 28 June 2018 29 June 2018

Please cite this article as: Xin Huang, Sheng Zhou, Ting Su, Lei Ye, Pei-Wen Zhu, WenQing Shi, You-Lan Min, Qing Yuan, Qi-Chen Yang, Fu-Qing Zhou, Yi Shao , Resting cerebral blood flow alterations specific to the comitant exophoria patients revealed by arterial spin labeling perfusion magnetic resonance imaging. Ymvre (2018), doi:10.1016/ j.mvr.2018.06.007

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ACCEPTED MANUSCRIPT Resting cerebral blood flow alterations specific to the comitant exophoria patients revealed by arterial spin labeling perfusion magnetic resonance imaging Xin Huang1*, Sheng Zhou2*, Ting Su3, Lei Ye1, Pei-Wen Zhu1, Wen-Qing Shi1,

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You-Lan Min 1, Qing Yuan 1, Qi-Chen Yang3, Fu-Qing Zhou4＃, Yi Shao2＃

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Running head: Cerebral blood-flow alterations in comitant exophoria patients 1

330006, Jiangxi, People’s Republic of China 2

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Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang

University, Guangzhou 510060, China 3

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The State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen

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Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and

Visual Science, Xiamen 361102, Fujian Province, China 4

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Department of Radiology, The First Affiliated Hospital of Nanchang University, DongHu District,

*

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Nanchang 330006, Jiangxi, People’s Republic of China

These authors have contributed equally to this work.

＃

Address correspondence to:

Yi Shao (Email: [email protected]; Tel: +086 791-88692520, Fax: +086 791-88692520), Department of ophthalmology, and Fu-Qing Zhou (Email: [email protected]; Tel: +791-88695132), Department of Radiology, The First Affiliated Hospital of Nanchang University, No 17, Yong Wai Zheng Street, DongHu District, Nanchang 330006, Jiangxi, People’s Republic of

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China;

ABSTRACT Purpose: It has been shown in many previous studies that there were significant

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changes of the brain anatomy and function in strabismus. However, the significance of the alterations of resting cerebral blood flow (CBF) in comitant exophoria (CE)

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remains obscure. Arterial spin labeling (ASL) MRI, which is a noninvasive method,

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could be applied to detect the cerebral blood flow quantitatively. Our study aimed to

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compare the resting CBF between the comitant exophoria and health controls using pseudo-continuous arterial spin labeling (pCASL) perfusion MRI method.

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Methods：32 patients (25 males and 7 females) with CE (study group), and 32 (25

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males and 7 females) healthy individuals with matched age and sex status (control

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group) underwent a whole-brain pCASL magnetic resonance (MR) examination at the resting state. The resting CBF were voxel-wise compared between the two groups

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using an analysis of variance designed in a statistical parametric mapping program.

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The CE patients were distinguishable from the healthy controls (HCs) by receiver operating characteristic (ROC) curves. Results: Compared with the control group, the CE group showed significantly increased resting CBF values in the right parahippocampal regions, bilateral medial frontal gyrus/anterior cingulate cortex, left inferior frontal gyrus, right inferior frontal gyrus, left superior frontal gyrus, bilateral medial cingulate cortex, right middle frontal gyrus, and right paracentral lobule.

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Conclusion:

Comitant

exophoria

showed

increased

resting

CBF

in

eye

movement-related brain areas including supplementary eye field, cingulate eye field and frontal eye field, which could be an explanation of the brain function

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compensation for the ocular motility disorders in the CE patients.

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Keywords: comitant exophoria (CE), pseudo-continuous arterial spin labeling

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(pCASL), cerebral blood flow (CBF), magnetic resonance imaging.

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1. Introduction The strabismus can be divided into congenital strabismus and acquired strabismus according to the onset time of the disease. Besides, the strabismus is divided into comitant or incomitant strabismus based on the angle of strabismus

[1]

The prevalence of the

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secondary strabismus due to blindness or ocular injury.

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roughly. Moreover, there are some ocular misalignment such as nystagmus and

[2]

The incidence of

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strabismus in preschool children is 5.65% in the Eastern China.

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intermittent exophoria is approximately 1 in 30 among Chinese preschool-aged children. [3]

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When the intermittent exophoria patient focuses on something near, the eye usually moves back to the centre. An eye intermittently turns outwards (exophoria),

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typically more when looking into the distance, when tired or day-dreaming. The occurrence of the strabismus is associated with many risk factors mainly include [4]

and cataract.

[5]

) and a extraocular muscle

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visual abnormality (refractive errors

pulleys abnormal [6] or nerve dysfunction [7]. The regular eye movements play a major

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role in binocular vision. A previous study reported that normal stereopsis was linked to binocular vision.

[8]

In clinic, strabismus does not only cause the ocular motor

disorder, but also lead to the loss of stereo and visual fusion function. [9] The visual stimulus activates the retino-cortical visual pathway and the retino-tectal visual pathway. The ocular motor is controlled by the cortex, the superior colliculus (SC) is controlled by the posterior parietal cortex (PPC) and more

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specifically parietal eye field (PEF) for triggering reflexive movements

[10]

and the

frontal eye field (FEF) for intentional movements [11], while the supplementary eye field (SEF) plays a role in movement preparing

[12]

. PEF is also involved in visual

attention and in spatial updating of visual information [13]. The SEF and FEF: involved

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in eye movement control by acting onto thalamus and the motor part (intermediate

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layer) of superior colliculus SC. Many previous studies demonstrated that the

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strabismus is not only related to abnormal eye muscles, [14] but also disorganization of

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the structure and dysfunction of brain. A previous study showed the impairment in visual cortex in macaque monkeys with infantile esotropia.

[15]

Diffusion tensor

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imaging (DTI) was used to reveal the alternations of brain white matter. The FA value is an index of DTI, it measures the overall directionality of water diffusion and

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reflects the complexity of cytoskeleton architecture. Another research reported that the comitant extropia is associated with lower white matter volumes and fractional

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anisotropy (FA) values in the right middle occipital gyrus.

[16]

Additionally, our

previous study suggested that comitant strabismus showed decreased amplitude of

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low-frequency fluctuation (ALFF) values in the bilateral medial frontal gyrus.

[17]

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abovementioned researches mainly focused on the brain function and structural changes in patients with strabismus. However, little is known about the altered cerebral blood flow in the comitant exotropia. Magnetic resonance (MR) perfusion imaging technique with arterial spin labeling (ASL) is a noninvasive and reliable perfusion imaging method, which has

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been used to assess the regional CBF.

[18,19]

The ASL uses magnetically-labeled blood

as an endogenous tracer. [20] The ASL has been successfully applied to investigate the abnormal CBF changes in many diseases such as schizophrenia

[21]

, Alzheimer's

disease [22] and Parkinson Disease. [23]

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This study aimed to investigate the alteration of resting-state CBF in the comitant

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exophoria, which might provide some useful information to understand the underlying

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neural mechanisms of comitant exophoria.

2. Materials and Methods

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2.1. Subjects

Patients （ 25 males and 7 females ） with CEs were recruited from the

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Ophthalmology Department of the First Affiliated Hospital of Nanchang University in

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Jiangxi province of China. All of the CEs were congenital strabismus with family history and genetic risks. All of the CEs patients were examined by two experienced

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ophthalmologist. The criteria for CE include: 1) the youth exophoria patients with mean age is >18 years and exophoria with stereopsis defects (no visual fusion); 2) the

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visual acuity (VA)>1.0 eye by eye; The exclusion criteria were: 1) conditions of eye diseases, trauma, or eye surgery; 2) conditions of psychiatric disorders (depressive disorder, delusional disorder), diabetes, cardiovascular disease, and any cerebral disease. Thirty-two healthy controls (HCs; 25 males, 7 females) with similar age range, sex ratio, and education status were enrolled in the study. All HCs met the following requirements: 1) normal brain parenchyma on cranial MRI; 2) visual acuity (VA) >1.0

ACCEPTED MANUSCRIPT and without any other ocular diseases (dry eye, strabismus, amblyopia, cataracts, glaucoma, optic neuritis, retinal degeneration, etc.); 3) no psychiatric disease (depressive disorder, delusional disorder); and 4) accessible to the MRI scanning (e.g. no cardiac pacemaker or implanted metal devices).5) no cardiovascular system diseases such as heart disease and hypertension;

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All research methods were approved by the committee of the medical ethics of

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the Ophthalmology Department of the First Affiliated Hospital of Nanchang

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University. All subjects were explained the purpose, method, potential risks and

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signed an informed consent form.

2.2. MRI Data Acquisition

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MRI was performed on a 3.0 Tesla (T) system (Magnetom TRIO, Siemens Medical). High resolution T1-, T2-imaging sequences were performed with the

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following parameter (TR =1,900 ms, TE =2.26 ms, thickness =1.0 mm, gap =0.5 mm,

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FOV =250 mm ×250 mm, matrix =256×256, flip angle =9°, 176 sagittal slices). Pseudocontinuous ASL (pCASL) was performed with the following parameters:

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60 Hanning window-shaped radio frequency pulses with duration 0.5 ms and space between radiofrequency pulses of 0.9 ms; flip angle, 90°; slice-selective gradient, 6

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mT/m; tagging duration (τ), 1720 ms; PLD, 1500 ms; and TR/TE, 4000 ms/18 ms 92 volumes. Fourteen axonal slices with 6 mm thickness were placed parallel to the anterior-posterior commissure line. We used a pCASL sequence that should provide good signal-to-noise ratio (SNR) and reduce sensitivity to transit time effects when delta T is sufficiently small with respect to T1 of blood.

2.3. Analysis of MRI Data

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ASL images were preprocessed using the pipeline implemented in ASLtbx (http://www.cfn.upenn.edu,).

[24]

The first step was motion correction (MoCo)

[25]

and

denoising. Denoising included spatial smoothing with an isotropic Gaussian at full-width-at-half-maximum (FWHM) of 4 mm3, temporal filtering using a high-pass

[26]

(FMRIB Software Library, Functional

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skull was stripped using the FSL BET

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Butterworth filter (cutoff frequency = 0.01 Hz) and temporal nuisance cleaning. The

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Magnetic Resonance Imaging of the Brain Centre, University of Oxford, Oxford, UK)

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tool to generate a brain mask. This mask was then used to extract the global mean signal time course, excluding extracranial voxels. Temporal nuisances including head

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motion time courses (3 translations and 3 rotations), the global signal time course, the WM mean signal time course, and the CSF mean signal time course were regressed

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out from ASL image series at each voxel 2. The next step was pair-wise subtraction and CBF quantification using the one-compartment model [27] implemented in ASLtbx.

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Gray matter, white matter, and CSF probability maps for each subject were generated from the anatomical images. The high-resolution structural images were first

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subsampled to the resolution of the functional images. Then, tissue segmentation algorithm provided in SPM8 (Wellcome Trust Centre for Neuroimaging, University College London, UK) was used to generate the gray matter, white matter and CSF probability maps for the subsampled structural images. ASL images were converted into units of blood flow (ml/100g/min) with MATLAB (2012a, The MathWorks, Natick, MA) using a single compartment flow

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model

[28]

. Deformation parameters generated in the segmentation step were used to

transform CBF maps into MNI space.

2.4. Ophthalmic testing

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The Snellen vision chart was used for visual tests analysis. All subjects were kept

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5 meters from vision chart and the gaze was kept parallel with the vision chart 1.0.

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2.5. Statistical analysis

The cumulative clinical measurements, including the duration of the onset of

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CEs, were analyzed with an independent sample T-test using SPSS version 16.0 (SPSS Inc, Chicago, IL, USA). (P <0.05 were considered as significantly different).

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A one-sample t-test was performed to extract the CBF results across the subjects within each group (P<0.05). Statistical analysis was performed with a general linear

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model analysis using the SPM8 toolkit. The two-sample t-tests were used to examine the differences in the CBF maps between the CEs groups and the health controls

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(two-tailed, voxel-level p <0.01, Gaussian random field theory (GRF) correction, cluster-level p < 0.05) The mean CBF values in the different brain regions between the two groups were analyzed by the receiver operating characteristic (ROC) curves method. Pearson correlation was used to evaluate the relationship between the mean CBF values in different brain regions in the CEs group and behavioral performances (P <0.05

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significant differences).

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3. Results 3.1. Demographics and visual measurements There were no obvious differences in weight (p=0.483), age (p=0.316), VA-Right (p=0.253) and best-corrected VA-Left (P=0.164) between the patients with CEs and

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the HCs. Details are presented in Table 1.

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3.2. Analysis of resting cerebral blood flow

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[Table 1]

Mean resting blood flow showed group-averaged whole brain resting CBF maps

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for each session (Figure1). There was no significant difference between sessions. Similarly, no significant differences of voxel-wise CBF changes were detected.

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T-test were used to compare the CBF maps differences between the CEs group and HC group. Compared with the control group, the CBF values of the CE group

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showed significant increase in the right parahippocampal regions, bilateral medial frontal gyrus/anterior cingulate cortex, left inferior frontal gyrus, right inferior frontal

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gyrus, left superior frontal gyrus, bilateral medial cingulate cortex, right middle frontal gyrus, and right paracentral lobule (Figure2 and Table2) (voxel level P < 0. 01 and cluster level P < 0.05, Gaussian random field (GRF) theory corrected). [Figure 1] [Figure 2] [Table 2]

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3.3. Receiver operating characteristic curve We identified brain regions with different CBF values between the CE groups and HC groups. The areas under the curve (AUC) was used to diagnose the quantity

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of the results. In the case of AUC > 0.5, the closer to 1, the higher accuracy of the

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result. AUC in 0.5 ~ 0.7 means low accuracy, AUC in 0.7 ~ 0.9 means middle

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accuracy, AUC in higher accuracy at above 0.9. In our study, the areas under the curve

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(AUC) were as follows: 0.827 for the right parahippocampal; 0.823 for the bilateral medial frontal gyrus/middle frontal gyrus; 0.764 for the left inferior frontal gyrus;

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0.791for the right inferior frontal gyrus; 0.779 for the left superior frontal gyrus; 0.742 for the bilateral medial cingulate cortex; 0.786 for the right middle frontal gyrus;

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0.751 for the right paracentral lobule (Figure3).

4. Discussion

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[Figure 3]

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The ASL is a noninvasive and reliable technique to measure cerebral blood flow. In our study, the CE groups showed significantly increased CBF values in the right parahippocampal regions, bilateral medial frontal gyrus/anterior cingulate cortex, left inferior frontal gyrus, right inferior frontal gyrus, left superior frontal gyrus, bilateral medial cingulate cortex, right middle frontal gyrus, and right paracentral lobule [Figure 4].

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[Figure 4]

The well oculomotor system was based on the six extraocular muscles, the parietal cortex and the frontal cortex related to eye fields such as supplementary eye

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field (SEF), cingulate eye field (CEF) and frontal eye fields (FEF). A previous study [29 ,30]

Besides, the SEF

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reported that the FEF was related to saccadic eye movement.

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was associated with saccade initiation.[31,32]

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The visual stimulus activates the retino-cortical visual pathway (LGN: lateral geniculate nucleus; visual cortex), which activates associative cortex (PPC, SEF and

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FEF) and subcortical areas (CN: caudate nucleus; SNpr: substantia nigra pars reticulata) involved in eye movement control by acting onto thalamus and the motor

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part (intermediate layer) of superior colliculus (SCi). Besides, the visual stimulus activates the retino-tectal visual pathway through the sensory part (superficial layer)

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of superior colliculus (SCs) coinstantaneously, which activates SCi directly. Eye movements are also triggered by premotor (Premot.), which are under the inhibitory

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control of omnipause neurons (OPN). Premotor neurons activate motor neurons of oculomotor (III), trochlear (IV) and abducens (VI) nerves. The supplementary eye field (SEF) is a cortical area within medial frontal cortex the medial frontal cortex is involved in the controlling of eye-head gaze shifts. [33,34] The SEF plays a critical role in the saccadic eye movements. behavior.

[37]

[35] [36]

Besides, the SEF is involved in goal-directed

In addition, the SEF plays an important role in proactive preparation of

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sequential saccades.

[38]

A recent study revealed that SEF is involved in the

unconscious and involuntary motor processes.

[39]

Our previous study found that the

comitant strabismus showed significant decreased ALFF values in the bilateral medial frontal gyrus, indicating the impairment of the bilateral SEF in the comitant [17]

However, in this study, we demonstrated that the CEs had marked

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strabismus.

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increased CBF values in the bilateral medial frontal gyrus, reflecting the hyperactivity

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in the SEF. We speculated that the CEs might be associated with functional

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reorganization in SEF.

The anterior cingulate cortex ACC (BA32) is a core part of the dorsal anterior

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cingulate area. A previous study demonstrated that the ACC play an important role in the cognitive saccade tasks.[40] Besides, the ACC is a key component of a network that

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directs both spatial attention and saccadic eye movements.[41] The ACC, also known as the cingulate eye field (CEF), plays an important role in the motivation and the

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preparation of all intentional saccades. [42] Additionally, the ACC is directly associated with the brain stem to control the eye movement. [43] A previous study reported that

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the infantile esotropia patients showed higher BOLD signal in the left cingulate gyrus compared with the healthy group. [44] Meanwhile, our recent report demonstrated that the comitant strabismus had increased mean diffusivity value in the left ACC.

[45]

In

support of these findings, we demonstrated in this study that the CEs had significantly higher resting CBF values in the bilateral ACC, reflecting enhanced activity in these brain regions. We concluded that the CEs might be associated with the ACC

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hyperfunction for compensation of the eye movement control disorder. The middle frontal gyrus (BA8) is known as the frontal eye fields (FEF). It located in the frontal cortex and is responsible for the saccadic eye movements.

[46]

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previous research demonstrated that electrical microstimulation of FEF leads to the

[48]

Moreover, frontal eye field lesions cause the dysfunction

Additionally, the FEF plays an important role in the spatial

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of oculomotor.

[47]

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saccadic eye movements.

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attention. [49] Chan ST et al reported that gray matter volume in the adult strabismus is

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dramatically higher than the health control, which might indicate the compensation for the oculomotor regions in strabismus. [50] Our previous study showed significantly

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increased mean diffusivity value in the right middle frontal gyrus in the comitant strabismus patients [45] Consistent with these findings, we found that the CEs also had

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significant increased CBF in the right middle frontal gyrus (BA8) and superior frontal gyrus, which might suggest a hyperactivation in this brain area. We hypothesize that

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the CEs might be associate with the FEF hyperfunction for the compensation of the ocular motor disorder.

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Meanwhile, we exhibited that the CEs showed higher CBF in the bilateral inferior frontal gyrus (IFG, BA47). The IFG played an important role in the linguistic and word experience.

[51,52]

Besides, the right IFG was associated with the inhibition

and attentional control. [53] A previous study demonstrated that the IFG might be relate to the in stopping initiated response.

[54]

Yan X et al reported that the comitant

strabismus showed increased fractional anisotropy (FA) values in the right inferior

ACCEPTED MANUSCRIPT frontal gyrus.[16] Thus, we speculated that the CEs might be associate with the impaired inhibition control function. In our study, the increased CBF values in supplementary eye field, cingulate eye field and frontal eye field were observed in comitant exophoria patients. Visual

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motion information for smooth pursuit is carried in dorsal stream pathways involving

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V5 and their connections with the upplementary eye field (SEF), cingulate eye field

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(CEF) and frontal eye fields (FEF). Comitant exophoria is associated with binocular

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visual impairment, which may triger brain areas of eye motor control. The increased CBF values in these eye motor- related brain regions may indicate the brain function

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compensation for the ocular motility disorders in the CE patients. 5. Conclusion

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In summary, our results suggested that CEs showed increased resting CBF distributions in eye movement-related brain areas including supplementary eye field，

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cingulate eye field and frontal eye fields, which might give an explanation of brain

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function compensation for the ocular motility disorders in the CE patients.

Limitations

However, there are some limitations to our study, such as the relatively small sample size. Moreover, the duration of the onset CEs for all patients was not exactly the same, which might affect the accuracy of the results. Meanwhile, the selected subjects were mainly concentrated in young age range. In the future study, the

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different CBF pattern occurred in infant strabismus and CEs would be revealed. The multi-modal fMRI methods would be used to investigate the neural mechanism of

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CEs.

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Acknowledgments This work was supported by the National Natural Science Foundation of China (No: 81660158 ， 81160118, 81400372); Jiangxi Province Voyage Project (No: 2014022); Natural Science Key Project of Jiangxi Province (No: 20161ACB21017);

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Youth Science Foundation of Jiangxi Province (No: 20151BAB215016); Technology

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and Science Foundation of Jiangxi Province (No: 20151BBG70223); Health

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Development Planning Commission Science Foundation of Jiangxi Province (No:

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Conflict of Interest Statement

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20175116)

This was not an industry supported study. The authors report no conflicts of

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interest in this work.

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Table 1. Demographics and clinical measures by group

CES

HC

t

P-value*

Male/female

25/7

25/7

N/A

N/A

Age (years)

24.56±1.96

25.16±2.68

-1.011

0.316

Weight (kg)

58.34±3.66

59.00±3.78

Handedness

32R

32R

Duration of strabismus (years)

22.25±2.21

N/A

VA-Right

1.20±0.20

VA-Left

1.18±0.18

0.483

N/A

N/A

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N/A

N/A

1.154

0.253

1.12±0.16

1.408

0.164

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-0.705

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1.14±0.19

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Condition

Notes: * Independent t-tests comparing two groups.

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Abbreviations: CEs, comitant exotropia strabismus; HCs, healthy controls; N/A, not applicable;

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CE

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VA, visual acuity.

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Table 2. Brain areas with significantly different CBF values between groups MNI coordinates

Peak voxels BA

x

y

z

22

12

-26

382

50

10

1647

CE> HC

4.297

32,10

B

4.625

601

47

L

3.934

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Cingulate cortex

R

RI

Medial Frontal Gyrus/Anterior 0

values

25,34

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ParaHippocampal

L/R

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Brain areas

T

-48

12

0

Inferior Frontal Gyrus

44

24

-6

847

47

R

3.950

Superior Frontal Gyrus

-16

36

48

258

9,8

L

3.892

Medial Cingulate cortex

0

142

23

B

3.947

D

24

22

48

360

8

R

4.186

16

-40

54

288

5

R

3.699

CE

Paracentral Lobule

24

-16

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Middle Frontal Gyrus

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Inferior Frontal Gyrus

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Notes: The statistical threshold was set at the voxel level with P < 0.05 for multiple comparisons using Gaussian Random Field (GRF) theory (z > 2.3, P < 0.01, GRF corrected). Abbreviations: CBF,cerebral blood flow; BA,Brodmann area; CEs, comitant exotropia strabismus; HCs, healthy controls;MNI, Montreal Neurological Institute; L, left; R, right; B, bilateral.

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Figure 1. Whole-brain voxel-wise CBF patterns in discogenic CE subjects (A) and HC subjects (B). The mean resting blood flow images in HCs and CEs in 2D (a and b). The mean resting blood flow images in HCs and CEs in 3D (c and d)

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strabismus;MNI, Montreal Neurological Institute;L,left; R,right.

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Abbreviations: CBF, cerebral blood flow, HCs, healthy controls;CEs, comitant exotropia

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Figure 2. CEs showed significant different brain regions compared with the health controls. Significant CBF differences were observed in the right parahippocampal regions, bilateral medial

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frontal gyrus/anterior cingulate cortex, left inferior frontal gyrus, right inferior frontal gyrus, left superior frontal gyrus, bilateral medial cingulate cortex, right middle frontal gyrus, right

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paracentral lobule; the red areas denote higher CBF values. (a and b) The means of altered CBF between the CEs and HCs. (c) (voxel level P < 0. 01 and cluster level P < 0.05, Gaussian random

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field (GRF) theory corrected.)

Abbreviations: CBF, cerebral blood flow, CEs, comitant exotropia strabismus; HCs, healthy

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controls.

Figure 3. ROC curve analysis of the mean CBF values for altered brain regions. Notes: The areas under the ROC curve were 0.827 (p<0.001; 95％CI: 0.720-0.933) for the RHP;0.823(p<0.001;95 ％ CI:0.715–0.931)for

the

BMFG/ACC;

0.764(p<0.001;

95 ％

CI:0.646–0.883) for the LIFG; 0.791(p<0.001;95％CI:0.675–0.908) for the RIFG; 0.779(p<0.001;

ACCEPTED MANUSCRIPT 95 ％CI: 0.662-0.896) for the LSFG;0.742(p<0.001; 95 ％CI: 0.615-0.869) for the BMCC; 0.786(p<0.001; 95％CI: 0.665-0.906) for the RMFG;0.751(p<0.001; 95％CI: 0.623-0.879) for the RPL; Abbreviations: ROC, receiver operating characteristic; CBF, cerebral blood flow; CI, confidence

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interval; HCs, healthy controls; CEs, comitant exotropia strabismus; HP, paraHippocampal; ACC,

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anterior Cingulate cortex; SFG, superior frontal gyrus; MFG, medial frontal gyrus/middle frontal

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gyrus; IFG, inferior frontal gyrus; MCC, medial cingulate cortex; PL, paracentral lobule;R,right; L,

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left; B, bilateral.

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Figure 4. The alterations of resting CBF values in comitant exophoria. Compared with the HCs group, the following regions showed significantly increased resting CBF values to various

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extents: 1-paraHippocampal regions (R) (BA25/34, t=4.297), 2-medial frontal gyrus/anterior cingulate cortex (B) (BA32/10, t=4.625), 3-inferior frontal gyrus (L) (BA47, t=3.934), 4-inferior

CE

frontal gyrus (R) (BA47, t=3.950), 5-superior frontal gyrus (L) (BA9/8, t=3.892), 6-medial cingulate cortex (B) (BA23, t=3.947), 7-middle frontal gyrus (R) (BA8, t=4.186), and

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8-paracentral lobule (R) (BA5, t=3.699) in CE patients. Abbreviations: CBF, cerebral blood flow; BA, Brodmann area; CE, comitant exotropia; HCs, healthy controls; L, left; R, right; B, bilateral. Notes: The sizes of the spots represent the degree of quantitative changes.

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Highlights: 1. The CE group showed significantly increased resting CBF values in the right parahippocampal regions, bilateral medial frontal gyrus/anterior cingulate cortex, left inferior frontal gyrus, right inferior frontal gyrus, left superior frontal gyrus,

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bilateral medial cingulate cortex, right middle frontal gyrus, and right paracentral

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lobule.

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2. Comitant exophoria showed increased resting CBF in eye movement-related

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brain areas including supplementary eye field, cingulate eye field and frontal eye field.

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3. The increased resting CBF values in eye movement-related brain areas could be an explanation of the brain function compensation for the ocular motility

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CE

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disorders in the CE patients.

Figure 1

Figure 2

Figure 3

Figure 4