To Explore The Alteration Of Brain Functional Network On Betel Quid Addiction By Using Resting-state Functional Magnetic Resonance Imaging

Background and ObjectionBetel quid(BQ)ranked the fourth most frequently consumed psychoactive substance around the globe,following only alcohol,nicotine,and caffeine in prevalence.BQ chewing is an important behavior from a public health perspective because it is associated with a variety of health issues,most notably oral cancer,esophageal cancer,liver cancer and cervical cancer and precancerous conditions such as leukoplakia and oral submucous fibrosis.Consequently,BQ has been categorized into a Group 1 carcinogen by the International Agency for Research on Cancer.The addictive characteristics of betel quid dependence are in line with the drug addiction summarized by World Health Organization:?desire and compulsion to seek and take the drug and loss of control in limiting intake;?the increasing trend of drug doses(tolerance);?the psychological and physiological dependence of addictive substances;?having a higher risk on individuals and society.Therefore,betel quid dependence in line with the Diagnostic and Statistical Manual of Mental Disorders(DSM-?;American Psychiatric Association,2000)and the ICD-10(World Health Organization,1992)belongs to the category of substance dependence,the same as tobacco and alcohol dependence.BQ use is associated with a dependency syndrome,which comprises increased concentration,mild euphoria,relaxation,postprandial satisfaction and a withdrawal syndrome associated with insomnia,mood swings,irritability and anxiety,the severity of which can be compared with that of amphetamine use.A few studies have assessed BQ dependence using adapted versions of dependence scales that were designed for substances other than BQ such as opioids or tobacco.Lee in Taiwan recently developed,and provided initial validation for,the first instrument designed specifically for measuring BQ dependence:the Betel Quid Dependence Scale(BQDS).BQDS is the first instrument designed specifically for measuring BQ dependence.The BQDS is comprised of three factors:"physical and psychological urgent need," "increasing dose," and "maladaptive use".The BQDS have assessed BQ dependence using approaches based upon the DSM-IV and ICD-10.The BQDS was found to have good internal consistency(a=.92)and construct validity.Although BQ is chewed by approximately 600 million people globally,its use is concentrated in South Asia,Southeast Asia,and Pacific islands.From prevention and treatment point of views,it is important to understand such reasons so that strategies may be developed to help individuals overcome an addiction.However,to date,most research on BQ chewing has been limited to epidemiological and biological investigations.Limited research has been conducted to understand the behavioral and psychological factors that lead individuals to initiate and/or maintain BQ chewing.With the rapid development of magnetic resonance imaging technology,research on substance dependence transition from the macro to the micro structure,metabolism and function of research,so that medical imaging diagnostic mode from the traditional morphology,gradually turned to modern imaging both with morphology and function.Functional magnetic resonance imaging is a non-invasive detection technology by far the most commonly used,with its high spatial and time resolution,non-invasive,non-radiation damage and can be repeated to detect in vivo,etc.Functional magnetic resonance imaging technology has been widely applied to the study of substance dependence related brain structure,metabolism and function.Pathological changes in the baseline brain can be evaluated using Resting-state functional MRI(Resting-state fMRI,rs-fMRI)without task design,which have been extensively used to study cognitive neuroscience and neuropsychiatric disorders.Through various kinds of data analysis methods,we are able to take advantage of spatial and temporal characteristics of brain activity.The connection of spontaneous fluctuations of blood oxygen level-dependent signals in diverse areas of the "resting" brain assesses the resting-state functional connectivity(rsFC)which is considered as a measure of its functional organization.Studies have outlined a number of resting-state networks corresponding to key brain functional organizations including vision,movement,language,audition,executive function,episodic memory,and salience detection.It is thought that the default mode network(DMN),the most famous resting-state network consisting of brain regions deactivated during external-oriented tasks,is involved in the maintenance of the baseline brain activities related to cognitions of self-awareness,episodic memory and interactive modulation between the interior mind activities and exterior tasks.The sensorimotor network(SMN),which is significant for the performance of voluntary movements,functionally connects regions within the primary motor cortex(M1)and the supplementary motor area(SMA).The affective network(AN)comprises a corticolimbic circuit responsible for negative emotional arousal or regulation and participates in autonomic and visceral functions.Respectively,the cognitive network(CN)and the visual network(VN)cope with corresponding cognition and vision functions.Therefore,in this study we detected whether there was alteration of functional connectivity related to ACC on samples with BQD for investigating the mechanisms underlying BQD.But ROI-based method is constrained by prior hypothesis.To overcome these shortcomings,analysis based on graph theory,such as functional connectivity density(FCD)mapping,is recommended for large-scale,bias-free,and prior-hypothesis-free whole brain network analysis.FCD mapping can be derived from degree centrality calculation by calculating degree centrality of each voxel in whole-brain cortex and subcortical area.The recent results of imaging studies indicate the prefrontal cortex,ventral tegmental area;nucleus accumbency,insula and so many brain districts may have the structural and functional damages in substance dependence patients,such as nicotine,alcohol,cocaine,heroin,etc.These studies lead to a more objective and scientific understanding of substance dependence.However,due to the geographical restrictions and defect awareness on betel quid dependence,there haven't had studies reported brain mechanisms of betel quid dependence.Limited research has been concentrated on pharmacology and behavioral research.So,what kind of impact betel quid dependence on the brain function network of the relatively weak addictive substance?Betel quid acting on brain regions in the brain and "illegal addictive substances" are the same?The objectives of this study is to explore different aspects of brain function connectivity in betel quid dependence patients using different Functional MRI analysis tools,and its relationships with the severity and duration of betel quid dependence were analyzed.Further explore the neural mechanisms to improve our understanding of betel quid dependence,provide a scientific basis for intervention and treatment of betel quid dependence.There are two parts in this dissertation.Part ?.Betel quid dependence is associated with functional connectivity changes of the anterior cingulate cortex:a resting-state fMRI studyObjective:It is generally acknowledged that drug dependence is connected with abnormal functional organization in the individual's brain.The present study aimed to identify the anterior cingulate cortex(ACC)abnormality with the cerebral networks involved in betel quid dependence(BQD)by resting-state functional connectivity(rsFC)using functional magnetic resonance imaging(fMRI).Methods:Persons with usage of BQ at least one day at a time for no less than 5 year and BQDS>4 without tobacco or any other drug addiction were categorized as "Betel Quid Dependence".Persons without usage of BQ,areca nut and tobacco(in all forms)were defined as "healthy control".MRI data were obtained on a Siemens Verio3T MRI scanner using a standard 6-channel head coil(Erlangen,Germany)in the Department of Radiology,People's hospital of Hainan Province.Whole-brain functional images were acquired with a T2*-weighted EPI sequence sensitive to BOLD contrast.A high-resolution T1-weighted structural image was acquired using a MPRAGE sequence.The toolbox Data Processing Assistant for Resting-State functional MR imaging(DPARSF;http://www.restfmri.net/forum/DPARSF)were used for the preprocessing of fMRI imaging data through statistical parametric mapping(SPM8;http://www.fil.ion.ucl.ac.uk/spm/)and an rs-fMRI data analysis toolkit(REST1.8;http://www.restfmri.net).WFU PickAtlas Tool Version 3.0(http://fmri.wfubmc.edu/software/PickAtlas)was adopted to define the seed region of bilateral ACC.The automated anatomical labeling(AAL)atlas offered in this toolbox was adopted to define the ROI of bilateral ACC which was used to define the reference time series with the method discussed in previous rs-fMRI studies.Functional connectivity analyses were carried out using the REST software.The reference time course was acquired by computing the mean time series for ROI.Cross-correlation was then analyzed between the mean signal change in the ACC and the time series of every voxel of whole brain.Lastly,we applied a Fisher Z-transform for the purpose of improving the normality of the correlation coefficients.In order to rule out possible effects of factors such as global,WM,and CSF signals,six head motion parameters and their mean time series were included in the regression analysis.Within each group,a random effect one-sample t test was performed on an individual Z value map in a voxel-wise manner to determine brain regions showing significant functional connectivity to the seed region of bilateral ACC.Significant thresholds were set at a corrected P<0.05 with multiple sample correction using false discovery rate(FDR)criterion across the whole brain.To identify regions with a significant difference in connectivity to the bilateral ACC in a voxel-wise manner,we entered these individual Z values into the SPM8 software for random-effects analysis two-sample t tests.For the purpose of controlling for the possible influences of factors including age,sex and education years on the results,such factors were included as nuisance covariates.We set the thresholds at a corrected P<0.01,with multiple comparisons correction using the AlphaSim program determined by Monte Carlo simulation(P<0.05,a minimum 22 clusters).Correlation analysis between the BQDS,duration and the fMRI data was accomplished.Results:At last,33 BQD volunteers and 32 HC individuals successfully obtained 3D structural imaging recruited from a residential area of Wanning City of Hainan province,China were included.The average age of the BQD sample was 46.7±9.4 years;The BQD group was 72.7%male,and had completed 12.3±2.7 year's education;Individuals indicated that they had been chewing BQ with dependency syndrome for a mean duration of 20.6±6.9 years(range 7 to 31 years),a mean BQDS of 10±3.4(range 5 to 16)and consumed an average of 342±106g/day BQ(range 200 to 500 g/day)daily.BQD chewers placed BQ in their mouth for an average of 7.6±2.4 minutes(range3 to 12)before spitting-out the remnants.There was no difference for the age,sex,education years,monthly income,alcohol last 30 days and SAS between the BQD patients and HC(P values>0.05);however,the BQD patients had a lower SDS score than HC(t=2.385,P=0.020).Compared with healthy control subjects,the individuals with BQD indicated significant increases in the FC between bilateral ACC and pons,between bilateral ACC and caudate,between bilateral ACC and bilateral thalamus,between bilateral ACC and midbrain,between bilateral ACC and cerebellum.By contrast,bilateral ACC exhibited decreased functional connectivity to the medial prefrontal cortex(mPFC),the left precuneus,and the left paraHippocampal/hypothalamus.Critically,the right ACC maps are to a large extent sign-inverted version of the left ACC maps.In BQD individuals,the functional connectivity of right ACC to left thalamus and left ACC to the pons were significantly and specifically positively correlated with BQDS(r=0.459;P=0.007;r=0.359;P=0.040).In addition,the functional connectivity of right ACC to the left precuneus were negatively associated with durations(r=-0.403,P=0.020).The other increased or decreased functional connectivity to the ACC were separated from BQDS and durations.Conclusions:Individuals with BQD develop increased ACC functional connectivity to the areas of the reward network and decreased to the DMN,especially increasedfunctional connectivity in the right ACC-left thalamus and left ACC-pons,may,therefore,represent a biomarker of BQD individuals.Additionally,disturbances in functional connectivity during resting state from ACC to the whole brain revealed by fMRI may have a key function in providing insights into the neurological pathophysiology underlying BQD-associated executive dysfunction and disinhibition.Such results may contribute to our better understanding of the mechanisms of BQD.Part ?.Altered long-and short-range functional connectivity in patients with betel quid dependence:a resting-state functional MRI studyObjective:It is generally acknowledged that drug dependence is connected with abnormal functional organization in the individual's brain.The present study aimed to evaluate the alteration of long-and short-range functional connectivity density(FCD)in betel quid dependence(BQD)patients by utilizing resting-state functional magnetic resonance imaging(rs-fM RI).Methods:33 BQD patients and 32 healthy controls(HCs)well-matched over age,gender,and education were studied.The rs-fMRI examination was performed to all of the 33 patients and HCs.The functional connectivity density(FCD)maps of both long-and short-range derived from degree centrality calculation were compared.Correlation analyses were conducted in the BQD group to investigate the relationship between the FCD measured by the two approaches(long-range FCD/short-range FCD)and the Betel Quid Dependence Scale(BQDS)and duration of BQD.Results:Compared with HCs,BQD patients mainly exhibited that long-range FCD was decreased in right anterior cingulate cortex(ACC)and increased in left cerebellum posterior lobe(CPL)and bilateral inferior parietal lobule(IPL).With respect to short-range FCD,we found a reduction in right ACC and left dlPFC,while an increase in left CPL.We also found BQDS showed negative correlation with short-range FCD in right ACC and duration showed positive correlation with long-range FCD in left IPL.Conclusions:In conclusion,the prominent FCD alteration was found mainly in brain areas related to DMN(right rostral ACC/bilateral IPL),reward circuit(right ACC/dlPFC)and cerebellum,which might reflect the neural plasticity of cerebellar functional network caused by BQD,also support the theory of reduction the monitoring function of the BQD patients.Spontaneous brain activity changes in right ACC and left IPL may be as a stable functional imaging quantitative index of betel quid dependence severity.The detailed mechanisms,implications of these brain activities and networks exhibiting changes will require further investigation.Brief SummaryThe objectives of this study is to explore different aspects of brain function connectivity in betel quid dependence patients using different Functional MRI analysis tools,and its relationships with the severity and duration of betel quid dependence were analyzed.In this study we detected whether there was alteration of functional connectivity related to ACC on samples with BQD for investigating the mechanisms underlying BQD.But ROI-based method is constrained by prior hypothesis.To overcome these shortcomings,analysis based on graph theory,such as functional connectivity density(FCD)mapping,is recommended for large-scale,bias-free,and prior-hypothesis-free whole brain network analysis.FCD mapping can be derived from degree centrality calculation by calculating degree centrality of each voxel in whole-brain cortex and subcortical area.The main results obtained are as follows:1.Individuals with BQD develop increased ACC functional connectivity to the areas of the reward network and decreased to the DMN,especially increased functional connectivity in the right ACC-left thalamus and left ACC-pons,may,therefore,represent a biomarker of BQD individuals.Additionally,disturbances in functional connectivity during resting state from ACC to the whole brain revealed by fMRI may have a key function in providing insights into the neurological pathophysiology underlying BQD-associated executive dysfunction and disinhibition.Such results may contribute to our better understanding of the mechanisms of BQD.2.The prominent FCD alteration was found mainly in brain areas related to DMN(right rostral ACC/bilateral IPL),reward circuit(right ACC/dlPFC)and cerebellum,which might reflect the neural plasticity of cerebellar functional network caused by BQD,also support the theory of reduction the monitoring function of the BQD patients.Spontaneous brain activity changes in right ACC and left IPL may be as a stable functional imaging quantitative index of betel quid dependence severity.