Reduced Coupling of Global Brain Activity and Cerebrospinal Fluid Flow in Individuals With Betel Quid Dependence.

ObjectiveThis study aimed to investigate brain spontaneous neural activity changes in betel quid dependence (BQD) chewers using the percent amplitude of fluctuation (PerAF) method.MethodsThis study included 48 BQD chewers. The healthy control (HC) group comprised 35 volunteers who were matched with BQD chewers in age, gender, and educational status. All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) and neuropsychological tests. The PerAF method was used to identify BQD-related regional brain activity changes. An independent samples t-test was used to evaluate the PerAF difference across two groups. The association between PerAF changes and clinical features such as BQD scores, duration of BQD, Hamilton Depression Rating Scale-24 item (HAMD-24), and Hamilton Anxiety Rating Scale-14 item (HAMA-14) was evaluated by using Spearman's correlation analysis. It assessed the ability of the PerAF method to distinguish between BQD chewers and HCs using a receiver operating characteristic (ROC) curve.ResultsCompared to the control group, BQD chewers showed decreased PerAF in right anterior cingulate cortex (ACC), right middle frontal gyrus (MFG), right insula, right precuneus, left putamen, left supramarginal gyrus (SMG), and left cerebellum and increased PerAF in right orbitofrontal and left superior temporal gyrus (STG) [P < 0.05, Gaussian random field (GRF) corrected]. PerAF values of the right MFG and right ACC had a significant negative relationship with the duration of BQD (P < 0.05). The average values of PerAF in the left putamen, left cerebellum, and left STG showed significant discriminatory power in distinguishing BQD chewers from HCs, with relatively prime area under the curve (AUC) values.ConclusionOur findings suggested that betel quid chewing is associated with spontaneous neural activity alterations in the impulsivity areas (MFG and ACC), cognitive (MFG, ACC, precuneus, and the cerebellum), and reward (orbitofrontal, putamen, and insula) systems, which may be correlated with neuropathological mechanisms of BQD. Also, PerAF may be useful as a potential sensitive biomarker for identifying spontaneous brain activity changes in BQD chewers.

Betel quid (BQ) is the fourth most popular psychoactive agent worldwide. Neuroimaging studies have showed that substance-addicted individuals including alcohol, heroin, nicotine and other addictive substance exhibit altered activity patterns of the salience network (SN). However, no study has yet investigated the neural correlates of the resting-state SN and BQ dependence (BQD)-related physiopathological characteristics. Thirty-two BQ-dependent (BQD) chewers and 32 healthy controls were recruited to participate in this study. Resting-state functional magnetic resonance imaging (fMRI) data were analysed by independent component analysis (ICA). BQD chewers exhibited decreased functional connectivity in bilateral insula, anterior cingulate cortex (ACC), medial superior frontal gyrus (MSFG) and inferior orbital frontal gyrus (IOFG) [false discovery rate (FDR) correction, p < 0.05]. In the BQD group, the decreased functional connectivity in left ACC correlated negatively with BQDS (BQD Scale) and the duration of BQ. We reported decreased functional connectivity in resting-state SN of BQD individuals. The decreased functional connectivity in left ACC correlated negatively with BQDS and the duration of BQ. Our findings provided evidence for the importance of the SN in the pathophysiology of BQD and indicated that the SN dysfunction might provide a potential mechanism in BQD development.

AimsSocial culture concerns and betel quid (BQ) dependence may be the potential reasons for BQ chewing. This study’s purpose was to identify the correlates of reasons for male BQ chewing.MethodsWe adopted a mixed-methods design. The study was conducted between October 2021 and August 2023 at a medical center of northern Taiwan. The Reasons for Betel-Quid Chewing Scale, Numeric Rating Scale, and Betel Quid Dependence Scale were used to quantitatively assess reasons for BQ chewing, stress, and BQ dependence, respectively. Semi-structured questions were used to interview for qualitative data.ResultsAmong 150 BQ users, the most common reasons for BQ chewing were stimulation, reinforcement, and social/cultural factors. Chewers who reported more pressure to chew were more likely to be younger, have less educational level, be employed, have greater stress, and have more BQ dependence. Content analysis of qualitative data showed three themes: physical and psychological demands, peer pressure, and perceived greater effectiveness.ConclusionEmployment was the factor most commonly associated with reasons for BQ chewing and with each construct. Study findings can help healthcare professionals understand reasons for BQ chewing, thereby helping them educate chewers to cope with withdrawal symptoms and successfully quit.

‘Dissolve flatulence and phlegm, ease hangover, facilitate digestion, eliminate toxins from overindulgence of fat and sweet foods, gourmet for everyone to enjoy.’ 1 ‘Many more studies now provide evidence for the carcinogenicity of betel quid without tobacco for oral cancer and for betel quid with tobacco for cancers of the oral cavity, pharynx and oesophagus.’ 2 However, when the eastern stimulant betel-quid is put under the scope of modern western addiction theory and methodology, the façade is peeled away. One notorious downside is that betel-quid is identified as a human carcinogen by the World Health Organization 2. Another dark side that is, as yet, little known concerns the probable dependence symptoms that betel-quid chewers may develop in terms of DSM-IV and ICD-10 criteria 3-6. Lee et al. 6 conducted a large-scale survey across six Asian countries to investigate betel-quid dependence symptoms and syndrome among betel-quid chewers. Three primary conclusions can be drawn from their study. First, betel-quid dependence prevalence among chewers varies largely across countries. Secondly, the amount and frequency of betel-quid consumption are critical factors that positively predict the risk of dependence. Thirdly, tobacco additives in betel-quid increase the risk of dependence in Sri Lankan chewers. The research conducted by Lee et al. 6 has at least two advantages: (i) a large sample was recruited and (ii) various betel-quid types and ingredients were evaluated. A large sample size allowed the researchers to perform higher-level statistical analysis, facilitating the understanding of complicated relationships between dependence and chewing characteristics. Types and ingredients of betel-quid vary across countries. For example, tobacco is usually added by Nepalese and Indonesian chewers, while slaked lime and betel leaf are used by Taiwanese chewers. Because various ingredients and types of betel-quid were included in Lee et al.'s study, they had the ability to investigate whether these ingredients and types, in addition to being solely tobacco-additive 3, affect the risk of dependence. However, Lee et al. 6 may have overlooked the influence of tobacco smoking on betel-quid dependence. This influence was observed in a survey of chewers in Malaysia, Indonesia and Sri Lanka who chewed both tobacco-added and tobacco-free betel-quids. Only in Sri Lankan chewers did tobacco additives increase the dependence risk. Why was this relationship between tobacco additive and dependence risk not observed in Malaysian and Indonesian chewers? The proportion of tobacco smokers in the tobacco-added and tobacco-free chewers may be a key issue, which was not investigated further by Lee and colleagues. In Malaysian and Indonesian chewers, there was a larger (and significant) proportion of tobacco smokers among the tobacco-free chewers than the tobacco-added chewers. Conversely, in Sri Lankan chewers, the proportions of tobacco smokers in both types of betel-quid were equivalent. It is possible that the proportion of tobacco smokers among the chewers may affect betel-quid dependence. Specifically, not only is the tobacco additive in betel-quid, but the tobacco smoked can affect betel-quid dependence. Betel-quid and tobacco are often used concurrently 7, 8. Neurologically, arecoline (one of the primary chemical ingredients of betel-quid) and nicotine have been shown to act on the muscarinic and nicotinic acetylcholine receptors 9, 10. Because of the concurrent use and similar neurological mechanisms of betel-quid and tobacco, the cross-substitutability of tobacco-added betel-quid and tobacco smoking should be taken into consideration when betel-quid dependence is assessed. In addition to the large-scale epidemiological surveys, cognitive neuroscience provides important and intriguing theories and paradigms that can guide betel-quid researchers to investigate how betel-quid affects chewers' cognition and brain activity. While fruitful cognitive neuroscience studies on drugs and substances are familiar to the West, the same type of study on betel-quid is still very rare. Understanding chewers' cognition and brain activity can help medical practitioners understand why the chewers are addicted. For example, betel-quid chewing immediately concentrates visual attention 11, 12, and heavy (not light) chewers) pay more attention to betel-quid cues 13. Betel-quid chewing may affect brain areas involving addiction, as shown in other substances (e.g. the amygdala–striatal and pre-frontal control systems) 14, 15. With knowledge of the neurological mechanisms of using betel nuts, more effective treatment plans can be developed. When eastern betel-quid encounters western addiction theories, together they may bring new insights into betel-quid use. Researchers have come a long way in understanding betel-quid and addiction research, but there is a long way to go. None.

Betel quid dependence(BQD)is a chronic recurrent brain disease characterized by loss of self-control and compulsive repeated use of drugs, which conforms to the characterics of addictive behavior classified by the World Health Organization.Long term chewing Betel nut can increase the risk of a variety of cancers such as oral cancer.The BQD research lacks the ideal animal model whereas the mechanism of BQD is still not clear, and there is no effective treatment and prevention. Notably, neuroimaging technology has provided a non-invasive, quantitative assessment method for the neural mechanism of BQD. The author summarized the neural mechanism and imaging studies progress of BQD, and these findings provided preliminary objective evidence for the brain changes of BQD, which was helpful for the deep understanding of the neuropathic mechanism of BQD, and provided theoretical basis for the early intervention and treatment. Key words: Betel quid dependence; Neural mechanism; Magnetic resonance imaging; Neuroimaging

Betel quid (BQ) ranks fourth in global self-administered psychoactive agents, after caffeine, alcohol and nicotine, with 600 million consumers. Patients with BQ dependence (BQD) disorder demonstrate deficits in executive function. However, the neural correlates of the resting-state executive control network (ECN) and BQD-related pathopsychological characteristics still remain unclear. The present study aimed to assess the functional and effective connectivity of the ECN using resting-state functional magnetic resonance imaging (rs-fMRI). Fifty-five BQD individuals and 54 healthy controls (HCs) were recruited in this study. The executive function of all participants was tested by three tasks. Independent component and Granger causal analysis were employed to investigate the functional connectivity within ECN and ECN-related directional effective connectivity, separately. Behavioural results suggested a marked deficit of executive function in BQD individuals. Compared with HCs, BQD individuals showed overall weaker functional connectivity in the ECN, mainly including dorsolateral prefrontal cortex (DLPFC), inferior parietal lobule (IPL) and middle frontal gyrus (MFG). We observed decreased outflow of information from the right DLPFC and IPL to the precentral/pre-supplement motor area (SMA) and increased outflow of information from the MFG to the middle occipital gyrus in BQD individuals. Correlation analysis revealed that the effective connectivity from IPL to precentral/pre-SMA was negatively correlated to the BQD scales in BQD individuals. Our findings revealed impaired executive function, functional connectivity of the ECN and causal interaction between networks in patients with BQD. These results could potentially direct future targets for the prevention and intervention of BQD.

Altered cerebral cortex's structural organization has been found in individuals with betel quid dependence (BQD). However, the neurological underpinnings of the BQD-related abnormalities in cortical thickness and brain circuitry deficit are largely unknown. This study aimed to investigate potential abnormalities of brain circuitry in the cortical thickness of BQD individuals by applying the surface-based morphometry (SBM) method. Cross-sectional study. High spatial resolution, three-dimensional T1-weighted structural imaging data were collected from 53 individuals with BQD and 37 healthy controls (HCs) who were similar to the BQD group in terms of age, sex, and educational level. The SBM method was applied to analyze the cortical thickness alterations in BQD-related areas. Independent-samples t-test was used to assess the cortical thickness difference between the two groups. Pearson correlation analysis was used to investigate the correlation between cortical thickness changes and clinical characteristics, including BQD scale scores and duration of BQD. The BQD group had a higher cortical thickness than the HC group at the lateral orbitofrontal (t = 4.703, p = 0.0028) and pars opercularis (t = 3.602, p = 0.0403) clusters in the right cerebral hemisphere, with age, sex, and education duration as covariates (p < 0.05, Monte Carlo). There were no significant differences in age, sex, or education duration-adjusted cortical thickness of the left cerebral hemisphere between BQD chewers and HCs (p > 0.05, Monte Carlo). Correlation analysis revealed that the cortical thickness of the right pars opercularis was negatively correlated with the BQD duration (r = -0.274, p = 0.047). The cortical thickness of the right lateral orbitofrontal cluster was not significantly correlated with Betel Quid Dependence Scale (BQDS) or BQD duration (p > 0.05). This study demonstrated that BQD might be associated with changes in the orbitofrontal and pars opercularis cortical thickness, which may be related to the neurobiological basis of BQD.

It has been suggested by the first voxel-based morphometry investigation that betel quid dependence (BQD) individuals are presented with brain structural changes in previous reports, and there may be a neurobiological basis for BQD individuals related to an increased risk of executive dysfunction and disinhibition, subjected to the reward system, cognitive system, and emotion system. However, the effects of BQD on neural activity remain largely unknown. Individuals with impaired cognitive control of behavior often reveal altered spontaneous cerebral activity in resting-state functional magnetic resonance imaging and those changes are usually earlier than structural alteration.Here, we examined BQD individuals (n = 33) and age-, sex-, and education-matched healthy control participants (n = 32) in an resting-state functional magnetic resonance imaging study to observe brain function alterations associated with the severity of BQD. Amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values were both evaluated to stand for spontaneous cerebral activity. Gray matter volumes of these participants were also calculated for covariate.In comparison with healthy controls, BQD individuals demonstrated dramatically decreased ALFF and ReHo values in the prefrontal gurus along with left fusiform, and increased ALFF and ReHo values in the primary motor cortex area, temporal lobe as well as some regions of occipital lobe. The betel quid dependence scores (BQDS) were negatively related to decreased activity in the right anterior cingulate.The abnormal spontaneous cerebral activity revealed by ALFF and ReHo calculation excluding the structural differences in patients with BQD may help us probe into the neurological pathophysiology underlying BQD-related executive dysfunction and disinhibition. Diminished spontaneous brain activity in the right anterior cingulate cortex may, therefore, represent a biomarker of BQD individuals.

BackgroundFindings from brain structural imaging studies on betel quid dependence have supported relations between betel quid chewing and alterations in gray matter volume and white matter integrity. However, the effect of betel quid chewing on cortical thickness and the link between cortical thickness and symptom severity remains unascertained.MethodsIn this observational study, we compared cortical thickness measures from 24 male betel quid-dependent chewers with 27 male healthy controls. Using FreeSufer, we obtained three-dimensional T1-weighted images that were used to compute the thickness of the cerebral cortex throughout the cortical layer.ResultsCompared to healthy controls, betel quid dependent chewers displayed significant decreased cortical thickness in the precuneus, entorhinal, right paracentral, middle temporal, and caudal middle frontal gyri. Betel quid dependence scale scores negatively correlated (r = -0.604; p = 0.002) with reduced cortical thickness in the right caudal middle frontal of betel quid-dependent chewers.ConclusionThe findings provide evidence for cortical thickness abnormality in betel dependent chewers and further propose that the severity of betel quid symptoms may be a critical aspect associated with the cortical alterations. The observed alterations may serve as potential mechanisms to explain why BQ chewing behavior is persistent among individuals with betel quid dependence.

Betel-quid (BQ) contains biologically psychoactive ingredients; however, data are limited concerning the symptoms and syndrome of BQ dependence among chewers. The aims of this study were to evaluate the ingredients-associated BQ dependence syndrome and country-specific chewing features and behaviour for BQ dependence among chewers from six Asian communities. An intercountry Asian Betel-quid Consortium study. Six Asian general communities in Taiwan, Mainland China, Indonesia, Malaysia, Sri Lanka and Nepal. Six multi-stage random samples of BQ chewers in the Asian Betel-quid Consortium study (n = 2078). All chewers were evaluated for BQ dependence using the DSM-IV and ICD-10 criteria. The 12-month BQ dependence rate was 12.5-92.6% and 47.9-99.3% (P = 0.023) among tobacco-free and tobacco-added BQ chewers across the six Asian communities, with a higher dependence rate in chewers who used tobacco-free BQ with lime added than without (23.3-95.6% versus 4.0%, P ≤ 0.001). Taiwanese and Hunanese BQ chewers both notably endorsed the dependency domain of 'time spent chewing'. 'Tolerance' and 'withdrawal' were the major dependence domains associated with the Nepalese and Indonesian chewers, with high BQ dependence rates. Malaysian and Sri Lankan chewers formed a BQ dependence cluster linked closely to 'craving'. In Sri Lanka, the quantity consumed explained 90.5% (P < 0.001) of the excess dependence risk for tobacco-added use, and could be a mediator between tobacco-derived psychoactive effect and BQ dependence development. DSM-IV criteria for dependence apply to a significant proportion of betel quid users in Asian communities, more so if they use it with tobacco or lime.

Betel quid dependence mechanism and potential cessation therapy

The Betel Quid Dependence Scale: Replication and extension in a Guamanian sample

Development and preliminary validation of a mandarin Chinese language questionnaire measuring betel quid dependency among adults in Taiwan

Recent studies have shown that substance dependence (addiction) is accompanied with altered activity patterns of the default mode network (DMN). However, the neural correlates of the resting-state DMN and betel quid dependence (BQD)-related physiopathological characteristics still remain unclear. Resting-state functional magnetic resonance imaging images were obtained from 26 BQD individuals and 28 matched healthy control subjects. Group independent component analysis was performed to analyze the resting state images into spatially independent components. Gray matter volume was examined as covariate with voxel-based morphometry to rule out its effect on the functional results. The severity of BQD was assessed by the BQD Scale (BQDS). We observed decreased functional connectivity in anterior part of the DMN including ventral medial prefrontal cortex, orbital MPFC (OMPFC)/anterior cingulate cortex (ACC). Furthermore, the functional connectivity within the OMPFC/ACC in BQD individuals was negatively correlated with BQDS (p = 0.01, r = -0.49). We reported decreased functional connectivity within anterior part of the DMN in BQD individuals, which provides new evidence for the role of the DMN in the pathophysiology of BQD.

Betel quid chewing poses significant public health risks across a range of countries from South to Southeast Asia, particularly in India. We aimed to identify factors influencing betel quid dependence (BQD) among consumers in a rural area of Southern India. A secondary aim was to find out which of the two instruments namely the Motivation to Stop Scale(MTSS), and Stages of Change Behavior scale was a better predictor of BQD among current betel quid users. 400 adult betel quid users were surveyed using the scales. We found that most of the participants were dependent on betel quid. BQD Scale scores increased with the participant’s age and the frequency of daily betel quid chewing and decreased with increasing educational attainment, being in the precontemplation stage, and having better self-perceived oral health status. Significant associations were observed between sociodemographic, behavioral, or psychosocial factors and betel quid dependence and the ‘Stages of Change’ model emerged as a useful predictor of dependency levels, more so than the MTSS scale, indicating its potential application in tailoring cessation interventions.