thecerebellumposteriorlobeassociateswiththe...

Research ArticleThe Cerebellum Posterior Lobe Associates with theExophthalmos of Primary Hyperthyroidism A Resting-StatefMRI Study

Wen-Feng Liu 1 Yong-Qiang Shu2 Pei-Wen Zhu 1 Biao Li1 Wen-Qing Shi1 Qi Lin1

Yu-Xin Liu1 Meng-Yao Zhang1 You-Lan Min1 Qing Yuan1 and Yi Shao 1

1Department of Ophthalmology e First Affiliated Hospital of Nanchang University Nanchang 330006 Jiangxi China2Department of Radiology e First Affiliated Hospital of Nanchang University Nanchang 330006 Jiangxi China

Correspondence should be addressed to Yi Shao freebee99163com

Received 20 May 2019 Revised 22 August 2019 Accepted 4 October 2019 Published 28 November 2019

Academic Editor Rosaria Meccariello

Copyright copy 2019Wen-Feng Liu et al-is is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Background Exophthalmos occurs in patients with primary hyperthyroidism -ere were few studies about the changes ofbrain functional networks of patients with exophthalmos of primary hyperthyroidism (EOPH) However differences inspontaneous brain activity in patients with EOPH remain unclear Objective -is study explored alterations in the brainfunctional networks of patients with EOPH using a voxel-wise degree centrality (DC) methodMethods A total of 20 patientswith EOPH (8 men and 12 women) were enrolled In addition 20 patients with primary hyperthyroidism without ex-ophthalmos matched in age sex and education status were enrolled as a control group -e Hospital Anxiety and De-pression Scale was used to assess the anxiety and depression status of participants All participants were examined usingresting-state functional MRI Changes in spontaneous brain activity were investigated using the DC method To distinguishbetween the DC values of the patients with EOPH and those of the control group we analyzed the receiver operatingcharacteristic (ROC) curve -e interrelationships between the DC values and clinical variables in the patients with EOPHwere evaluated using Pearsonrsquos correlation coefficient Results Patients with EOPH exhibited notably lower DC values in thecerebellum posterior lobe than the control group In addition there were negative correlations between the anxiety scores(AS) and the depression scores (DS) and DC values of the cerebellum posterior lobe-e ROC curve analysis of the cerebellumposterior lobe demonstrated that the area under the curve method had a high diagnostic accuracy Conclusions Our study wasthe first to our knowledge to explore changes in the brains of patients with EOPH using the DC method -e DC value wassignificantly different in the cerebellum posterior lobe in patients with EOPH indicating that the cerebellum posterior lobe isassociated with EOPH

1 Introduction

Primary hyperthyroidism is a common clinical syndromewhich is caused by excessive synthesis and release of thyroidhormones Moreover patients usually experience high met-abolic and sympathetic excitation [1 2] Many patients withprimary hyperthyroidism will develop typical eye symptomsincluding exophthalmos eyelid edema and visual loss ofwhich exophthalmos is one of the most significant and specificsigns [3 4] Figure 1 shows exophthalmos and nonprominenteyes in patients with primary hyperthyroidism

Exophthalmos of primary hyperthyroidism (EOPH) ischaracterized by extraocular muscle hypertrophy an increasein muscle tension and ocular movement disorder [5] -eocular protrusion of EOPH is greater than 18mm and EOPHoften progresses bilaterally [6] Because patients with EOPHcannot close their eyelids the conjunctiva and cornea areexposed to air easily leading to conjunctivitis and keratitisand even blindness Previous studies have shown that EOPHmight be associated with extraocular muscle hypertrophyretrobulbar tissue increase and the invasion of lymphocytes[7] However rarely research had focused on the intrinsic

HindawiInternational Journal of EndocrinologyVolume 2019 Article ID 8135671 8 pageshttpsdoiorg10115520198135671

brain activity variations of EOPH -e function and contri-bution of brain tissue are not yet fully determined Fortunatelybrain image scanning might promote noninvasive explorationof alterations in the brain functional networks of patients withEOPH

In recent years the development of neuroimagingtechnology has provided more possibilities for studying themechanism of neuropsychiatry-related diseases At the sametime the rapid development of fMRI has made it possible toprovide solid evidence that changes in brain regions areclosely related to several ophthalmological diseases Basedon the different magnetic properties of oxyhemoglobin anddeoxyhemoglobin blood-oxygen-level dependent signals ofdifferent brain regions are obtained while subjects remainrelaxed and awake with closed eyes [8 9] fMRI can be usedto indirectly search for specific brain activation areas ofsubjects and is a useful tool in determining the functionalconnectivity of the human brain Moreover the fMRI datacan also serve as the physiological basis for informationprocessing and mental representation

Voxel-wise degree centrality is one method of resting-state fMRI which measures the topological structure ofbrain functional connectors at the voxel level and detects thefunctional relationships between a brain region and the restof the brain [10] -e DC value represents the number ofdirect connections of a given voxel in the functional con-nector and a high DC value represents a node with sub-stantial direct connections to other nodes [11] -us DCvalues can objectively and comprehensively reflect the ab-normalities of brain functional areas -erefore DC is abetter network measurement than other methods More-over DC has been utilized to assess the altered brain activityin patients with epilepsy Parkinsonrsquos disease type-two di-abetes attention deficit hyperactivity disorder and Alz-heimerrsquos disease [12ndash16] Accordingly the DC method is adependable rs-fMRI technology which has not yet been usedin the study of EOPH In this study the DC method is usedto further understand converted spontaneous brain activitiesin patients with EOPH in comparison with patients withprimary hyperthyroidism without exophthalmos

2 Materials and Methods

21 Subjects A total of 20 patients with EOPH (8 men and12 women) were recruited from the First Affiliated Hospitalof Nanchang University China Inclusion criteria were asfollows (1) met the diagnostic criteria for primary hyper-thyroidism (2) exophthalmos confirmed by imaging ex-amination (3) bilateral exophthalmos (4) men were 18ndash60

years old while women were 18ndash50 years old (5) right-handedness Exclusion criteria were as follows (1) a historyof severe craniocerebral trauma (2) a history of epilepticseizures schizophrenia bipolar disorder or other mentaldisorders (3) a history of alcohol or drug abuse (4) otherendocrine diseases and autoimmune diseases besides hy-perthyroidism (5) pregnancy (6) claustrophobia or othercontraindications for magnetic resonance imaging

Twenty patients with primary hyperthyroidism withoutexophthalmos (8 men and 12 women) matched for age sexand education status were also recruited as control groupsfor this research Inclusion criteria were as follows (1) pri-mary hyperthyroidism (2) no symptoms of exophthalmos(3) no other endocrine diseases or autoimmune diseases (4)no history of alcohol or drug abuse (5) no history of neu-rological or psychiatric disorders (6) not pregnant (7) right-handedness and (8) no MRI scanning contraindications

-e study received approval from the Medical EthicsCommittee of the First Affiliated Hospital of NanchangUniversity and abided by the Declaration of Helsinki Allparticipants were informed of the objectives contents po-tential risks and signed informed consent forms

22 Parameters for MRI A 3-Tesla MR scanner (Trio Sie-mens Munich Germany) was used for MRI scanning Weacquired whole-brain T1 weights by using a spoiled gradient-recalled echo sequence with the following parametersrepetition time 1900ms echo time 226ms flip angle 9degthickness 10mm field of view 250mmtimes 250mm gap05mm and acquisition matrix 256times 256 -e scanningparameters were as follows repetition time 2000ms echotime 30ms flip angle 90deg thickness 40mm field of view220mmtimes 220mm gap 12mm acquisition matrix 64times 6429 axial slices and 240 volumes

23 Data Processing for fMRI MRIcro (httpwwwMRIcrocom) Statistical Parametric Mapping software (SPM8httpwwwfilionuclacukspm) the Data Processing As-sistant for rs-fMRI advanced edition (DPARSFA httprfmriorgDPARSF) software and the Resting-State DataAnalysis Toolkit (REST httpwwwrestfmrinet) were uti-lized to prefilter the data -e procedure of preprocessingincluded the following steps Firstly the first 10 volumes ofeach field are abandoned to achieve balance of the signal andadaptation of the participants Secondly the translation (inmillimeters) and rotation (in degrees) of each subject isestimated after head movement correction and volumeswith movements in the x y or z direction greater than 2mm

(a) (b)

Figure 1 Primary hyperthyroidism patients with exophthalmos (a) and without exophthalmos (b)

2 International Journal of Endocrinology

are excluded -en fMRI images were detrended andbandpass filtered (001ndash008Hz) to reduce effects of low-frequency drift and physiological high-frequency respiratoryand cardiac noise-en the fMRI images are standardized tothe Montreal Neurological Institute (MNI) using standardecho planar imaging templates and resampling at a reso-lution of 3mmtimes 3mmtimes 3mm

24 Degree Centrality On the basis of the individual voxel-wise functional network we calculated the DC value bycounting the number of degrees of the binarized adjacencymatrix or significant suprathreshold correlations betweenthe subjects and used the following equation to convert thevoxel DC diagram of each individual to a z-score map

zi DCi minusmeanallstdall

1113888 1113889 (1)

where zi refers to the z-score of the ith voxel DCi is the DCvalue of the ith voxel and stdall refers to the standard de-viation [17]

25 Correlation Analysis Graphpad prism 7 (GraphPadSoftware Inc San Diego CA USA) was then used to analyzethe correlation between DC mean values in altered brainareas and the clinical behaviors (plt 005 was taken to in-dicate significant difference)

26 Statistical Analysis -e demographic and clinical var-iables between the EOPH and control groups were com-pared using SPSS200 software (SPSS Chicago IL USA)with the independent samples t-test And plt 005 wasregarded as statistically significant -e statistical thresholdof the voxel level for multiple comparisons according to theGaussian random field (GRF) theory was set at a level ofplt 005 -e general linear model analysis generated by theSPM8 toolkit was used to investigate the difference in DCvalues between patients with EOPH and the control group-e receiver operating characteristic (ROC) curve methodwas used to distinguish the mean DC values in brain areas ofpatients with EOPH from those of control groups -ecorrelations between the DC values of cerebrum areas andthe clinical features in patients with EOPH were investigatedusing Pearsonrsquos correlation coefficient

3 Results

31 Demographics and Behavioral Results Twenty patientswith EOPH (8 men and 12 women) and 20 control grouppatients (8 men and 12 women) were involved in this study-ere was no statistically significant difference in patientsrsquoage sex or weight or in intraocular pressure between the twogroups However significant differences existed in the du-ration of hyperthyroidism (p 0046) the best-correctedright-eye visual acuity (p 0009) the best-corrected left-eye visual acuity (p 0012) and the anxiety (plt 0001) anddepression scores (plt 0001) in the two groups Details areshown in Table 1

32 Difference in DC -e DC value clearly decreased in thecerebellum posterior lobe in the EOPH group (Figures 2(a)and 2(b) and Table 2)-emean DC between the two groupsis shown in Figure 2(c)

33 Receiver Operating Characteristic (ROC) Curve In thisstudy the DC values of the cerebellum posterior lobe of theEOPH and control groups are different And the area underthe curve (AUC) of the cerebellum posterior lobe was 1000(Figure 3) -e area under the ROC curve represents thediagnostic rate AUC values of 05ndash07 indicate that thediagnostic value is limited AUC values between 07 and 09indicate a perfect diagnostic value and AUC values greaterthan 09 indicate high accuracy

34CorrelationAnalysis In the EOPH group anxiety scoresnegatively correlated with the DC values of the cerebellumposterior lobe (r minus 0794 plt 0001) depression scores alsonegatively correlated with the DC values of the cerebellumposterior lobe (r minus 0873 plt 0001) (Figure 4)

4 Discussion

Resting-state fMRI can effectively display spatial patterns oftemporal correlation -e DC method is a new and reliable rs-fMRI method for revealing changes in brain functional con-nectivity and detecting and quantifying activation sites in thebrain -is method has already been applied effectively in thestudy of various ocular diseases including glaucoma comitantexotropia strabismus late monocular blindness and open globeinjury (Figure 5) [18ndash21] As far as we know this is the first timethat the DC method has been used to identify changes in theendogenous functional connectivity on the basis of voxel-basedglobal brain correlation analysis in individuals with EOPH

In this study we demonstrated altered intrinsic brainconnectivity patterns of the cerebellum posterior lobe inindividuals with EOPH -e EOPH group exhibited sig-nificantly decreased DC signal values in the cerebellumposterior lobe In addition anxiety and depression scoreswere negatively correlated with DC values of the cerebellumposterior lobe (Figure 6)

-e cerebellum posterior lobe lies between the cerebellarfissure and the posterolateral fissure and occupies the greaterpart of the cerebellum in human beings -e function of thecerebellum posterior lobe is to influence the initiation planningand coordination of movement and determine the strengthdirection and scope of the movement [22 23] In additionstudies have consistently revealed that the cerebellum posteriorlobe is also responsible for nonmotor functions [24]

-e role of the cerebellum posterior lobe in eyemovement control and adaptation is well known [25] Whenperforming microstimulations on the cerebellums of ma-caque monkeys Fujikado and Noda [26] found that thecerebellum posterior lobe was responsible for saccadic eyemovements In another previous study Lisberger [27] usedthe concept of internal models which provided a conceptualstructure to help in understanding how the cerebellumcontrols eye movement In addition Colnaqhi and her

International Journal of Endocrinology 3

Table 1 Demographics and behavioral results of the EOPH group and control group

Condition EOPH Control group t p valueMalefemale 812 812 NA gt099Age (years) 5422plusmn 688 5391plusmn 671 0129 0916Weight (kg) 5699plusmn 632 5892plusmn 742 0091 0817Handedness 20R 20R NA gt099Duration of hyperthyroidism (yrs) 1132plusmn 521 1269plusmn 617 0072 0046Best-corrected Va in right eye 089plusmn 012 101plusmn 017 minus 0492 0009Best-corrected Va in left eye 092plusmn 016 103plusmn 013 minus 0385 0012IOP-R (mmHG) 2077plusmn 391 1914plusmn 189 0092 0782IOP-L (mmHG) 1989plusmn 412 2091plusmn 221 0088 0826AS 605plusmn 115 420plusmn 095 5555 lt0001DS 585plusmn 109 355plusmn 076 7746 lt0001Notes independent t-tests comparing the two groups (plt 005 represented statistically significant differences) EOPH exophthalmos of primary hyper-thyroidism NA not applicable Va visual acuity IOP intraocular pressure R right L left AS anxiety scores DS depression scores

ndash95mm

ndash75mm

ndash55mm

ndash35mm

ndash90mm

ndash70mm

ndash50mm

ndash30mm

ndash85mm

ndash65mm

ndash45mm

ndash25mm

ndash80mm

ndash60mm

ndash40mm

ndash20mm

0

50

CPL

T values

(a)

Figure 2 Continued


associates [28] applied transcranial magnetic stimulation totest cerebellar control of reflexive and voluntary eye move-ments proving that the cerebellum posterior lobe plays a keyrole in reflexive and voluntary eye movements Furthermorein research on concomitant strabismus patients the meandiffusivity values in bilateral posterior cerebellar lobes werefound using digital transducer interface technology to besignificantly decreased [29] In addition Tan et al [20] foundthat the DC value of the right posterior cerebellar lobe wasdecreased in patients with concomitant strabismus in-dicating that dysfunction of the posterior cerebellar lobe wasrelated to abnormal coordination of the extraocular musclesAll these facts prove that the cerebellum posterior lobe isclosely associated with eye movement regulation Consistentwith these findings we demonstrated decreased DC values inthe cerebellum posterior lobe in this study this finding mightreflect the reduction of the role and position of the cere-bellum posterior lobe in the whole-brain network in patientswith EOPH Furthermore we speculatively suggest that thechanged functional connectivity in the cerebellum posteriorlobemight be associated with eyemovement abnormalities inpatients with EOPH

However the cerebellum posterior lobe also plays a keyrole in emotion [30 31] Lou et al [32] found that the DCvalue in the cerebellum posterior lobe was decreased indepressed patients -erefore it was speculated that dys-function of the cerebellar posterior lobe might be related todepression In another study patients with obstructive sleepapnea exhibited complex and abnormal DC values in thecerebellum and other brain areas at rest [33] It has beenreported that obstructive sleep apnea patients also

0

556

(b)

Altered DC regionsCPL

EOPHControl

ndash10

ndash05

00

05

10

15

Mea

n D

C va

lues

(c)

Figure 2 Comparison ofDC in the EOPHgroup and control group (a) Significant difference inmeanDCvalues betweenEOPHand control groupwas recognized in the CPL (b) -e stereoscopic form of the cerebrum-e red regions indicated lower DC values AlphaSim corrected at a clustersize gt40 voxels and a level of plt 001 for multiple comparisons using Gaussian random field theory (c) -e mean DC values between the EOPHgroup and control group DC degree centrality EOPH exophthalmos of primary hyperthyroidism CPL cerebellum posterior lobe

Table 2 Significant difference in DC values in the cerebellumposterior lobe between EOPH group and control group

EOPH patients and control groups MNIcoordinates

Brain areas BA Tvalues

Peakvoxels x y z

Cerebellum posteriorlobe 556227 93 minus 15 minus 84 minus 27

Notes the statistical threshold was set at the voxel level with plt 005 formultiple comparisons using the Gaussian Random Field theory (zgt 23plt 001 cluster gt40 voxels AlphaSim corrected) DC degree centralityEOPH exophthalmos of primary hyperthyroidism MNI Montreal Neu-rological Institute BA Brodmann area

ROC curve

02 04 06 08 10001 ndash specificity

00

02

04

06

08

10

Sens

itivi

ty

Figure 3 ROC curve analysis of the mean DC values in thecerebellum posterior lobe-e area under the ROC curve was 1000(plt 0001 95 CI 100ndash100) for CPL ROC receiver operatingcharacteristic DC degree centrality EOPHs exophthalmos ofprimary hyperthyroidism groups


r = ndash0794 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065D

C va

lues

642 8 100AS

(a)

r = ndash0873 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065

DC

valu

es

2 4 6 8 100DS

(b)

Figure 4 Correlations between the mean DC values of the cerebellum posterior lobe and the clinical behaviors (a) -e AS showed anegative correlation with the DC values of the cerebellum posterior lobe (r minus 0794 plt 0001) and (b) the DS showed a negative correlationwith the DC values of the cerebellum posterior lobe (r minus 0873 plt 0001) DC degree centrality AS anxiety scores DS depression scores

Tan et al

Increase DC valuesRSTGBACLIPL

Decrease DC valuesRCPLRIFG

RMFGRSPL

Huang et alIncrease DC values Decrease DC values

LITGBMFG

BCBV1V2

Comitant exotropia strabismus

Ophthalmological diseases

Monocular blindness

Ope

n gl

obe

inju

ry

Wan

g et

al

Incr

ease

DC

valu

esBV

1V

2LP

CUN

Dec

reas

e DC

valu

esRI

RI

PLS

MG

RSM

ARP

G

Prim

ary

angl

e-cl

osur

egl

auco

ma

Cai e

t al

Incr

ease

DC

valu

esLA

CC

LC

Dec

reas

e DC

valu

esBV

C

Figure 5 DC method applied in ophthalmological diseases DC degree centrality RSTG right superior temporal gyrus BAC bilateralanterior cingulate LIPL left inferior parietal lobule RCPL right cerebellum posterior lobe RIFG right inferior frontal gyrus RMFG rightmiddle frontal gyrus RSPL right superior parietal lobule LACC left anterior cingulate cortex LC left cuneus BVC bilateral visual corticesLITG left inferior temporal gyrus BMFG bilateral medial frontal gyrus BC bilateral cuneus BV1V2 bilateral primary visual cortexLPCUN left precuneus RI right insula RIPLSMG right inferior parietal lobulesupramarginal gyrus RSMA right supplementary motorarea RPG right postcentral gyrus


experience depression and anxiety [34] -us the brainactivity change in the cerebellum posterior lobe might alsobe a basis of anxiety and depression Furthermore Gobelet al [35] reported that experimental thyrotoxicity couldlead to an increase in gray matter volumes in the left andright cerebellum posterior lobe Moreover the increase ingray matter volumes in the cerebellum posterior lobe wasthought to be compensatory for depression workingmemory and movement coordination In this study weused the Hospital Anxiety and Depression Scale to assess theanxiety and depression status of participants Our resultsshowed that patients with EOPH had higher anxiety anddepression scores than the control group In additionanxiety and depression scores were negatively correlatedwith DC values of the cerebellum posterior lobe It is likelythat the alteration of brain network centrality is also asso-ciated with impairment of the emotion procession in pa-tients with EOPH

-e AUC is often utilized to reflect diagnostic accuracy-e ROC result revealed that the AUC of the cerebellumposterior lobe was 1000 which suggested that there weresignificant differences in DC values between the EOPH andcontrol groups Consequently we inferred that the DC valueof the cerebellum posterior lobe might be a potential di-agnostic marker for patients with EOPH

Our research still has some limitations First of all ourstudy population is not very large More participants areneeded to further verify the results Furthermore the mo-lecular mechanism between the variation of cerebellumposterior lobe activity and exophthalmos in patients withhyperthyroidism needs further investigation

5 Conclusion

To sum up this study demonstrated that patients withEOPH had abnormal networks in their cerebellum posteriorlobe which indicates that the cerebellum posterior lobe is

associated with exophthalmos and provides insight into theneural variation in patients with EOPH

Data Availability

-e data used to support the findings of this study areavailable from the corresponding author upon request

Conflicts of Interest

-e authors declare that there are no conflicts of interestregarding the publication of this article

Authorsrsquo Contributions

Wen-Feng Liu and Yong-Qiang Shu contributed equally tothis work

Acknowledgments

-is work was supported by the National Natural ScienceFoundation of China (nos 81660158 81460092 and81400372) Natural Science Key Project of Jiangxi Province(no 20161ACB21017) and Health Development PlanningCommission Science Foundation of Jiangxi Province (no20175116)

References

[1] N M Intildeiguez-Ariza R A Lee N M Singh-OspinaM N Stan and M R Castro ldquoEthanol ablation for thetreatment of cystic and predominantly cystic thyroid nod-ulesrdquo Mayo Clinic Proceedings vol 93 no 8 pp 1009ndash10172018

[2] M Sharma W S Aronow L Patel K Gandhi and H DesaildquoHyperthyroidismrdquo Medical Science Monitor vol 17 no 4pp RA85ndashRA91 2011

[3] D L Weiler ldquo-yroid eye disease a reviewrdquo Clinical andExperimental Optometry vol 100 no 1 pp 20ndash25 2017

[4] J Lindholm and P Laurberg ldquoHyperthyroidism exoph-thalmos and goiter historical notes on the orbitopathyrdquoyroid vol 20 no 3 pp 291ndash300 2010

[5] P Kuanrakcharoen ldquoRadioiodine (1-131) dose for thetreatment of hyperthyroidism in rajavithi hospitalrdquo Journal ofthe Medical Association of ailand vol 99 no Suppl 2pp S123ndashS129 2016

[6] K Chatzistefanou C Samara I Asproudis et al ldquoSubcon-junctival orbital fat prolapse and thyroid associated orbit-opathy a clinical associationrdquo Clinical Interventions in Agingvol 12 pp 359ndash366 2017

[7] Y Wu B Tong Y Luo G Xie and W Xiong ldquoEffect ofradiotherapy on moderate and severe thyroid associatedophthalmopathy a double blind and self-controlled studyrdquoInternational Journal of Clinical and Experimental Medicinevol 8 no 2 pp 2086ndash2096 2015

[8] A Tang T Chen J Zhang Q Gong and L Liu ldquoAbnormalspontaneous brain activity in patients with anisometropicamblyopia using resting-state functional magnetic resonanceimagingrdquo Journal of Pediatric Ophthalmology amp Strabismusvol 54 no 5 pp 303ndash310 2017

[9] R Herold E Varga A Hajnal et al ldquoAltered neural activityduring irony comprehension in unaffected first-degree

Anxiety anddepression

Exophthalmos

Figure 6 Correlations between mean DC signal values and be-havioral performance Compared with the control group the DCvalue of the CPL was decreased in EOPH patients And the EOPHpatients exhibited with more anxiety and depression DC degreecentrality CPL cerebellum posterior lobe EOPH exophthalmos ofprimary hyperthyroidism


relatives of schizophrenia patients-an fMRI studyrdquo Frontiersin Psychology vol 8 p 2309 2018

[10] H-J Chen L-F Jiang T Sun J Liu Q-F Chen andH-B Shi ldquoResting-state functional connectivity abnormali-ties correlate with psychometric hepatic encephalopathy scorein cirrhosisrdquo European Journal of Radiology vol 84 no 11pp 2287ndash2295 2015

[11] G R Wu S Stramaglia H Chen W Liao and D MarinazzoldquoMapping the voxel-wise effective connectome in resting statefMRIrdquo PLoS One vol 8 no 9 Article ID e73670 2013

[12] X Wang D Jiao X Zhang and X Lin ldquoAltered degreecentrality in childhood absence epilepsy a resting-state fMRIstudyrdquo Journal of the Neurological Sciences vol 373pp 274ndash279 2017

[13] S-W Xue and Y Guo ldquoIncreased resting-state brain entropyin alzheimerrsquos diseaserdquo Neuroreport vol 29 no 4pp 286ndash290 2018

[14] Y Cui S-F Li H Gu et al ldquoDisrupted brain connectivitypatterns in patients with type 2 diabetesrdquo American Journal ofNeuroradiology vol 37 no 11 pp 2115ndash2122 2016

[15] Y Hou J Yang C Luo et al ldquoDysfunction of the defaultmode network in drug-naıve parkinsonrsquos disease with mildcognitive impairments a resting-state fMRI studyrdquo Frontiersin Aging Neuroscience vol 8 p 247 2016

[16] M A Di X-N Zuo C Kelly et al ldquoShared and distinctintrinsic functional network centrality in autism and atten-tion-deficithyperactivity disorderrdquo Biological Psychiatryvol 74 no 8 pp 623ndash632 2013

[17] X-N Zuo R Ehmke MMennes et al ldquoNetwork centrality inthe human functional connectomerdquo Cerebral Cortex vol 22no 8 pp 1862ndash1875 2012

[18] H Xin F Q Zhou Y L Zhong et al ldquoAltered brain networkcentrality in patients with late monocular blindness a resting-state fMRI studyrdquo Archives of Medical Science vol 32 no 1pp 1ndash18 2019

[19] H Wang T Chen L Ye et al ldquoNetwork centrality in patientswith acute unilateral open globe injury a voxel wise degreecentrality studyrdquo Molecular Medicine Reports vol 16 no 6pp 8295ndash8300 2017

[20] G Tan Z-R Dan Y Zhang et al ldquoAltered brain networkcentrality in patients with adult comitant exotropia strabis-mus a resting-state fMRI studyrdquo Journal of InternationalMedical Research vol 46 no 1 pp 392ndash402 2018

[21] F Cai L Gao H Gong et al ldquoNetwork centrality of resting-state fMRI in primary angle-closure glaucoma before and aftersurgeryrdquo PLoS One vol 10 no 10 Article ID e0141389 2015

[22] C Stoodley and J Schmahmann ldquoFunctional topography inthe human cerebellum a meta-analysis of neuroimagingstudiesrdquo NeuroImage vol 44 no 2 pp 489ndash501 2009

[23] M Glickstein P Strata and J Voogd ldquoCerebellum historyrdquoNeuroscience vol 162 no 3 pp 549ndash559 2009

[24] P L Strick R P Dum and J A Fiez ldquoCerebellum andnonmotor functionrdquo Annual Review of Neuroscience vol 32no 1 pp 413ndash434 2009

[25] D A Suzuki and E L Keller ldquo-e role of the posterior vermisof monkey cerebellum in smooth-pursuit eye movementcontrol I Eye and head movement-related activityrdquo Journalof Neurophysiology vol 59 no 1 pp 1ndash18 1988

[26] T Fujikado andH Noda ldquoSaccadic eye movements evoked bymicrostimulation of lobule VII of the cerebellar vermis ofmacaque monkeysrdquoe Journal of Physiology vol 394 no 1pp 573ndash594 1987

[27] S G Lisberger ldquoInternal models of eye movement in thefloccular complex of the monkey cerebellumrdquo Neurosciencevol 162 no 3 pp 763ndash776 2009

[28] S Colnaqhi S Ramat E DrsquoAngelo and M VersinoldquoTranscranial magnetic stimulation over the cerebellum andeye movements state of the artrdquo Funct Neurol vol 15 no 3pp 165ndash171 2010

[29] S Yi X Huang H-J Li et al ldquoMicrostructural changes of thewhole brain in patients with comitant strabismus evidencefrom a diffusion tensor imaging studyrdquo NeuropsychiatricDisease and Treatment vol 12 pp 2007ndash2014 2016

[30] J D Schmahmann ldquoDisorders of the cerebellum ataxiadysmetria of thought and the cerebellar cognitive affectivesyndromerdquo e Journal of Neuropsychiatry and ClinicalNeurosciences vol 16 no 3 pp 367ndash378 2004

[31] S H A Chen and J E Desmond ldquoTemporal dynamics ofcerebro-cerebellar network recruitment during a cognitivetaskrdquo Neuropsychologia vol 43 no 9 pp 1227ndash1237 2005

[32] Y Lou P Huang D Li et al ldquoAltered brain network cen-trality in depressed parkinsonrsquos disease patientsrdquo MovementDisorders vol 30 no 13 pp 1777ndash1784 2015

[33] H Li L Li Y Shao et al ldquoAbnormal intrinsic functional hubsin severe male obstructive sleep apnea evidence from a voxel-wise degree centrality analysisrdquo PLoS One vol 11 no 10Article ID e0164031 2016

[34] P M Macey M A Woo R Kumar R L Cross andR M Harper ldquoRelationship between obstructive sleep apneaseverity and sleep depression and anxiety symptoms innewly-diagnosed patientsrdquo PLoS One vol 5 no 4 Article IDe10211 2010

[35] A Gobel M Heldmann M Gottlich A-L Dirk G Brabantand T F Munte ldquoEffect of experimental thyrotoxicosis onbrain gray matter a voxel-based morphometry studyrdquo Eu-ropeanyroid Journal vol 4 no Suppl 1 pp 113ndash118 2015


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Submit your manuscripts atwwwhindawicom

brain activity variations of EOPH -e function and contri-bution of brain tissue are not yet fully determined Fortunatelybrain image scanning might promote noninvasive explorationof alterations in the brain functional networks of patients withEOPH

In recent years the development of neuroimagingtechnology has provided more possibilities for studying themechanism of neuropsychiatry-related diseases At the sametime the rapid development of fMRI has made it possible toprovide solid evidence that changes in brain regions areclosely related to several ophthalmological diseases Basedon the different magnetic properties of oxyhemoglobin anddeoxyhemoglobin blood-oxygen-level dependent signals ofdifferent brain regions are obtained while subjects remainrelaxed and awake with closed eyes [8 9] fMRI can be usedto indirectly search for specific brain activation areas ofsubjects and is a useful tool in determining the functionalconnectivity of the human brain Moreover the fMRI datacan also serve as the physiological basis for informationprocessing and mental representation

Voxel-wise degree centrality is one method of resting-state fMRI which measures the topological structure ofbrain functional connectors at the voxel level and detects thefunctional relationships between a brain region and the restof the brain [10] -e DC value represents the number ofdirect connections of a given voxel in the functional con-nector and a high DC value represents a node with sub-stantial direct connections to other nodes [11] -us DCvalues can objectively and comprehensively reflect the ab-normalities of brain functional areas -erefore DC is abetter network measurement than other methods More-over DC has been utilized to assess the altered brain activityin patients with epilepsy Parkinsonrsquos disease type-two di-abetes attention deficit hyperactivity disorder and Alz-heimerrsquos disease [12ndash16] Accordingly the DC method is adependable rs-fMRI technology which has not yet been usedin the study of EOPH In this study the DC method is usedto further understand converted spontaneous brain activitiesin patients with EOPH in comparison with patients withprimary hyperthyroidism without exophthalmos

2 Materials and Methods

21 Subjects A total of 20 patients with EOPH (8 men and12 women) were recruited from the First Affiliated Hospitalof Nanchang University China Inclusion criteria were asfollows (1) met the diagnostic criteria for primary hyper-thyroidism (2) exophthalmos confirmed by imaging ex-amination (3) bilateral exophthalmos (4) men were 18ndash60

years old while women were 18ndash50 years old (5) right-handedness Exclusion criteria were as follows (1) a historyof severe craniocerebral trauma (2) a history of epilepticseizures schizophrenia bipolar disorder or other mentaldisorders (3) a history of alcohol or drug abuse (4) otherendocrine diseases and autoimmune diseases besides hy-perthyroidism (5) pregnancy (6) claustrophobia or othercontraindications for magnetic resonance imaging

Twenty patients with primary hyperthyroidism withoutexophthalmos (8 men and 12 women) matched for age sexand education status were also recruited as control groupsfor this research Inclusion criteria were as follows (1) pri-mary hyperthyroidism (2) no symptoms of exophthalmos(3) no other endocrine diseases or autoimmune diseases (4)no history of alcohol or drug abuse (5) no history of neu-rological or psychiatric disorders (6) not pregnant (7) right-handedness and (8) no MRI scanning contraindications

-e study received approval from the Medical EthicsCommittee of the First Affiliated Hospital of NanchangUniversity and abided by the Declaration of Helsinki Allparticipants were informed of the objectives contents po-tential risks and signed informed consent forms

22 Parameters for MRI A 3-Tesla MR scanner (Trio Sie-mens Munich Germany) was used for MRI scanning Weacquired whole-brain T1 weights by using a spoiled gradient-recalled echo sequence with the following parametersrepetition time 1900ms echo time 226ms flip angle 9degthickness 10mm field of view 250mmtimes 250mm gap05mm and acquisition matrix 256times 256 -e scanningparameters were as follows repetition time 2000ms echotime 30ms flip angle 90deg thickness 40mm field of view220mmtimes 220mm gap 12mm acquisition matrix 64times 6429 axial slices and 240 volumes

23 Data Processing for fMRI MRIcro (httpwwwMRIcrocom) Statistical Parametric Mapping software (SPM8httpwwwfilionuclacukspm) the Data Processing As-sistant for rs-fMRI advanced edition (DPARSFA httprfmriorgDPARSF) software and the Resting-State DataAnalysis Toolkit (REST httpwwwrestfmrinet) were uti-lized to prefilter the data -e procedure of preprocessingincluded the following steps Firstly the first 10 volumes ofeach field are abandoned to achieve balance of the signal andadaptation of the participants Secondly the translation (inmillimeters) and rotation (in degrees) of each subject isestimated after head movement correction and volumeswith movements in the x y or z direction greater than 2mm

(a) (b)

Figure 1 Primary hyperthyroidism patients with exophthalmos (a) and without exophthalmos (b)





1113888 1113889 (1)




3 Results





4 Discussion








ndash95mm

ndash75mm

ndash55mm

ndash35mm

ndash90mm

ndash70mm

ndash50mm

ndash30mm

ndash85mm

ndash65mm

ndash45mm

ndash25mm

ndash80mm

ndash60mm

ndash40mm

ndash20mm

0

50

CPL

T values

(a)

Figure 2 Continued




0

556

(b)


EOPHControl

ndash10

ndash05

00

05

10

15

Mea

n D

C va

lues

(c)





Peakvoxels x y z



ROC curve


00

02

04

06

08

10

Sens

itivi

ty



r = ndash0794 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065D

C va

lues

642 8 100AS

(a)

r = ndash0873 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065

DC

valu

es

2 4 6 8 100DS

(b)


Tan et al



RMFGRSPL


LITGBMFG

BCBV1V2



Monocular blindness

Ope

n gl

obe

inju

ry

Wan

g et

al

Incr

ease

DC

valu

esBV

1V

2LP

CUN

Dec

reas

e DC

valu

esRI

RI

PLS

MG

RSM

ARP

G

Prim

ary

angl

e-cl

osur

egl

auco

ma

Cai e

t al

Incr

ease

DC

valu

esLA

CC

LC

Dec

reas

e DC

valu

esBV

C






5 Conclusion



Data Availability






Acknowledgments


References











Exophthalmos



































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






















1113888 1113889 (1)




3 Results





4 Discussion








ndash95mm

ndash75mm

ndash55mm

ndash35mm

ndash90mm

ndash70mm

ndash50mm

ndash30mm

ndash85mm

ndash65mm

ndash45mm

ndash25mm

ndash80mm

ndash60mm

ndash40mm

ndash20mm

0

50

CPL

T values

(a)

Figure 2 Continued




0

556

(b)


EOPHControl

ndash10

ndash05

00

05

10

15

Mea

n D

C va

lues

(c)





Peakvoxels x y z



ROC curve


00

02

04

06

08

10

Sens

itivi

ty



r = ndash0794 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065D

C va

lues

642 8 100AS

(a)

r = ndash0873 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065

DC

valu

es

2 4 6 8 100DS

(b)


Tan et al



RMFGRSPL


LITGBMFG

BCBV1V2



Monocular blindness

Ope

n gl

obe

inju

ry

Wan

g et

al

Incr

ease

DC

valu

esBV

1V

2LP

CUN

Dec

reas

e DC

valu

esRI

RI

PLS

MG

RSM

ARP

G

Prim

ary

angl

e-cl

osur

egl

auco

ma

Cai e

t al

Incr

ease

DC

valu

esLA

CC

LC

Dec

reas

e DC

valu

esBV

C






5 Conclusion



Data Availability






Acknowledgments


References











Exophthalmos



































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of





















ndash95mm

ndash75mm

ndash55mm

ndash35mm

ndash90mm

ndash70mm

ndash50mm

ndash30mm

ndash85mm

ndash65mm

ndash45mm

ndash25mm

ndash80mm

ndash60mm

ndash40mm

ndash20mm

0

50

CPL

T values

(a)

Figure 2 Continued




0

556

(b)


EOPHControl

ndash10

ndash05

00

05

10

15

Mea

n D

C va

lues

(c)





Peakvoxels x y z



ROC curve


00

02

04

06

08

10

Sens

itivi

ty



r = ndash0794 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065D

C va

lues

642 8 100AS

(a)

r = ndash0873 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065

DC

valu

es

2 4 6 8 100DS

(b)


Tan et al



RMFGRSPL


LITGBMFG

BCBV1V2



Monocular blindness

Ope

n gl

obe

inju

ry

Wan

g et

al

Incr

ease

DC

valu

esBV

1V

2LP

CUN

Dec

reas

e DC

valu

esRI

RI

PLS

MG

RSM

ARP

G

Prim

ary

angl

e-cl

osur

egl

auco

ma

Cai e

t al

Incr

ease

DC

valu

esLA

CC

LC

Dec

reas

e DC

valu

esBV

C






5 Conclusion



Data Availability






Acknowledgments


References











Exophthalmos



































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of





















0

556

(b)


EOPHControl

ndash10

ndash05

00

05

10

15

Mea

n D

C va

lues

(c)





Peakvoxels x y z



ROC curve


00

02

04

06

08

10

Sens

itivi

ty



r = ndash0794 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065D

C va

lues

642 8 100AS

(a)

r = ndash0873 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065

DC

valu

es

2 4 6 8 100DS

(b)


Tan et al



RMFGRSPL


LITGBMFG

BCBV1V2



Monocular blindness

Ope

n gl

obe

inju

ry

Wan

g et

al

Incr

ease

DC

valu

esBV

1V

2LP

CUN

Dec

reas

e DC

valu

esRI

RI

PLS

MG

RSM

ARP

G

Prim

ary

angl

e-cl

osur

egl

auco

ma

Cai e

t al

Incr

ease

DC

valu

esLA

CC

LC

Dec

reas

e DC

valu

esBV

C






5 Conclusion



Data Availability






Acknowledgments


References











Exophthalmos



































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















r = ndash0794 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065D

C va

lues

642 8 100AS

(a)

r = ndash0873 p lt 0001

ndash085

ndash080

ndash075

ndash070

ndash065

DC

valu

es

2 4 6 8 100DS

(b)


Tan et al



RMFGRSPL


LITGBMFG

BCBV1V2



Monocular blindness

Ope

n gl

obe

inju

ry

Wan

g et

al

Incr

ease

DC

valu

esBV

1V

2LP

CUN

Dec

reas

e DC

valu

esRI

RI

PLS

MG

RSM

ARP

G

Prim

ary

angl

e-cl

osur

egl

auco

ma

Cai e

t al

Incr

ease

DC

valu

esLA

CC

LC

Dec

reas

e DC

valu

esBV

C






5 Conclusion



Data Availability






Acknowledgments


References











Exophthalmos



































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






















5 Conclusion



Data Availability






Acknowledgments


References











Exophthalmos



































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















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