- [Show abstract] [Hide abstract] ABSTRACT: Background Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. In the present study, we introduced a technique to target all diverse cues associated with an aversive event that causes fear. Methods In the human experiments, 161 subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In the animal experiments, 343 rats underwent contextual fear conditioning under a similar protocol as the used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Results We found that presentation of a lower-intensity US following extinction disrupted the associations between the different CSs and reactivated US in both humans and rats. This effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of AMPA glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. Conclusions These findings demonstrate that a modified US retrieval-extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear.
- [Show abstract] [Hide abstract] ABSTRACT: The nucleus accumbens (NAc) is a key part of the neural circuitry that creates reward, pleasure and motivation that facilitates human feeding, sexual and smoking behaviors. In the brain reward system, the NAc is a crucial component responsible for natural and drug-induced reinforcement behaviors. Yet it is unclear whether NAc is indispensible for all reward behaviors in human beings. The present study aimed to investigate the long-term effects of NAc ablation on sexual function, appetite, and nicotine dependence level in chronic heroin users. Eighteen former heroin-dependent patients (male) with bilateral NAc ablation via stereotactic radiofrequency surgery for alleviating drug psychological dependence were recruited. Their postoperative time ranged from 12 to 103 months. All subjects received MRI scans for assessing the accuracy of the lesion site. Evaluation of appetite, sexual function, and nicotine dependence were measured using the Simplified Nutrition Appetite Questionnaire, the Brief Sexual Function Inventory, and the Fagerstrom Test for Nicotine Dependence, respectively. After precluding the potential confounding variables, such as drug use (dosage and duration), post-operation duration, age, body-weight, marital status and education level, ANOVA with repeated measures revealed that the NAc ablation improved the patients' appetite, sexual drive and sexual satisfaction. Yet there was no change in male erectile function, ejaculatory function, or nicotine dependence levels compared to the preoperative. These may suggest that although NAc is a key part of the neural circuitry, the NAc surgical lesions left the fundamental aspects of natural and drug-induced reinforcement and motivation almost intact.
Dataset: Figure S1[Show abstract] [Hide abstract] ABSTRACT: Correlation maps between signal changes in the left MPFC and IPL, which were significantly activated among heroin-dependent patients by heroin-related cues, and the abstinence duration ( P <0.05, corrected for Monte Carlo simulations; r : correlation coefficient). (TIF)
Dataset: Table S1[Show abstract] [Hide abstract] ABSTRACT: Activated brain regions for the SA group in response to heroin-related vs. neutral cues. (DOC)
- [Show abstract] [Hide abstract] ABSTRACT: The brain activity induced by heroin-related cues may play a role in the maintenance of heroin dependence. Whether the reinforcement or processing biases construct an everlasting feature of heroin addiction remains to be resolved. We used an event-related fMRI paradigm to measure brain activation in response to heroin cue-related pictures versus neutral pictures as the control condition in heroin-dependent patients undergoing short-term and long-term abstinence. The self-reported craving scores were significantly increased after cue exposure in the short-term abstinent patients (t = 3.000, P = 0.008), but no increase was found in the long-term abstinent patients (t = 1.510, P = 0.149). However, no significant differences in cue-induced craving changes were found between the two groups (t = 1.193, P = 0.850). Comparing between the long-term abstinence and short-term abstinence groups, significant decreases in brain activation were detected in the bilateral anterior cingulated cortex, left medial prefrontal cortex, caudate, middle occipital gyrus, inferior parietal lobule and right precuneus. Among all of the heroin dependent patients, the abstinence duration was negatively correlated with brain activation in the left medial prefrontal cortex and left inferior parietal lobule. These findings suggest that long-term abstinence may be useful for heroin-dependent patients to diminish their saliency value of heroin-related cues and possibly lower the relapse vulnerability to some extent.
- [Show abstract] [Hide abstract] ABSTRACT: Stress in adolescence has been widely demonstrated to have a lasting impact in humans and animal models. Developmental risk and protective factors play an important role in the responses to stress in adulthood. Mild-to-moderate stress in adolescence may resist the negative impacts of adverse events in adulthood. However, little research on resilience has been conducted. In the present study, we used a predictable chronic mild stress (PCMS) procedure (5 min of daily restraint stress for 28 days) in adolescent rats (postnatal days 28-55) to test the resilience effect of PCMS on depressive-like behavior in the sucrose preference test and forced swim test and anxiety-like behavior in the novelty-suppressed feeding test and elevated plus maze in adulthood. We also investigated the role of mammalian target of rapamycin (mTOR) signaling in the brain during the PCMS procedure in adolescence. Moreover, we investigated the effect of PCMS in adolescence on subsequent responses to chronic unpredictable stress (CUS; postnatal days 63-83) in adulthood. The results demonstrated that PCMS during adolescence produced antidepressant- and anxiolytic-like effects and increased mTOR signaling activity in the prefrontal cortex in early adulthood. Either systemic administration or intra-PFC infusion of the mTOR inhibitor rapamycin completely blocked the behavioral effects produced by PCMS in adolescence. PCMS during adolescence resisted depressive- and anxiety-like behavior caused by CUS in adulthood. These findings indicate that PCMS in adolescence can contribute to resilience against depression and anxiety caused by stress in adulthood.Neuropsychopharmacology accepted article preview online, 11 March 2013; doi:10.1038/npp.2013.67.
- [Show abstract] [Hide abstract] ABSTRACT: Craving is an important factor in relapse to drug abuse, and cue-induced craving is an especially powerful form of this construct. Neuroimaging methods have been utilized to study drug cue-induced craving and neural correlates in the human brain. However, very few studies have focused on characterizing craving and the neural responses to heroin-related cues in short-term abstinent heroin-dependent patients. Twenty-four heroin-dependent subjects and 20 demographically matched drug-naïve subjects participated in this study. An event-related cue-reactivity paradigm was employed, while changes in blood oxygen level-dependent (BOLD) signals were acquired by functional magnetic resonance imaging (fMRI). The heroin-dependent group reported significantly increased craving following exposure to heroin-related cues. Direct comparison between the two groups showed that brain activation to heroin-related minus neutral cues was significantly greater for the heroin-dependent group in the bilateral nucleus accumbens (NAc), caudate, putamen, amygdala, hippocampus/parahippocampus, midcingulate cortex, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC), medial frontal gyrus (MeFG), midbrain, thalamus, left anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and subcallosal gyrus. Changes in craving in the heroin-dependent group correlated positively with brain activation in the bilateral NAc, caudate, right putamen, and left ACC. The abstinence duration correlated positively with brain activation in the left caudate and right parahippocampal gyrus. In conclusion, the cue-reactivity paradigm significantly activated neural responses in the mesolimbic dopamine (DA) system and prefrontal cortex (PFC) and induced increased craving in short-term abstinent heroin-dependent patients. We suggest that these response patterns characterize the high vulnerability of relapse in short-term abstinent heroin-dependent subjects.
- [Show abstract] [Hide abstract] ABSTRACT: PURPOSE We applied functional magnetic resonance imaging (fMRI) to investigate the subjective craving and brain response to heroin-related cues in heroin-dependent males. We also try to seek how the heroin-related cues impact the addicts, localize the heroin craving related brain regions, and try to supplement on the theory of the cerebral responses to the heroin cues. METHOD AND MATERIALS Sixteen heroin-dependent subjects and 15 demographically matched healthy controls completed an event-related fMRI task including heroin-related and neutral cues. The fMRI data were acquired by a 3T MRI system and preprocessed and statistically analyzed by the Matlab 7.5, SPM5 software package. Self-reported craving scores were collected before and after the task. For the heroin-dependent subjects, correlation analyses were performed on craving changes and the difference in fMRI responses between heroin-related and neutral images for each region of interest (ROI) which was determined by the comparison between heroin addicts and healthy controls under the condition (heroin-related vs. neutral cues). Correlation analyses between characteristics of heroin use (the daily heroin dose, the total amount of heroin used and heroin history) and the difference in fMRI response between heroin-related and neutral images for each ROI were also performed. RESULTS Direct comparison between the two groups showed that brain activation to heroin-related minus neutral cues was significantly greater for heroin group in the bilateral nucleus accumbens, subcallosal gyrus, caudate, putamen, medial dorsal thalamus, periaqueductal gray, medial frontal cortex, superior frontal gyros, inferior frontal gyrus, parahippocampal gyrus, amygdala, anterior cingulate cortex(ACC) and left hippocampus, posterior cingulate cortex. No greater activation was found in the control group compared with heroin group. The total heroin duration was respectively negatively correlated with the activation of left ACC and amygdala. CONCLUSION We have further approved that the prefrontal, mesocorticolimbic regions and thalamus play an important role in visual heroin-related cue induced reactivity in heroin addicts and long-term heroin use impair the brain regions implicated in cognitive control and affective processes. CLINICAL RELEVANCE/APPLICATION fMRI is non-invasive and useful for investigation of heroin dependence and it may provide deep insight into the mechanism of heroin dependence for people.
- [Show abstract] [Hide abstract] ABSTRACT: Cigarette smoking is highly prevalent in the general population but the effects of chronic smoking on brain structures are still unclear. Previous studies have found mixed results regarding regional grey matter abnormalities in smokers. To characterize both grey and white matter changes in heavy male smokers, we investigated 16 heavy smokers and 16 matched healthy controls, using both univariate voxel-based morphometry (VBM) and multivariate pattern classification analysis. Compared with controls, heavy smokers exhibited smaller grey matter volume in cerebellum, as well as larger white matter volume in putamen, anterior and middle cingulate cortex. Further, the spatial patterns of grey matter or white matter both discriminated smokers from controls in these regions as well as in other brain regions. Our findings demonstrated volume abnormalities not only in the grey matter but also in the white matter in heavy male smokers. The multivariate analysis suggests that chronic smoking may be associated with volume alternations in broader brain regions than those identified in VBM analysis. These results may better our understanding of the neurobiological consequence of smoking and inform smoking treatment.
- [Show abstract] [Hide abstract] ABSTRACT: Recent studies have documented declined global cognitive function and abnormal task-related brain activation in chronic cigarette smokers. However, the effects of long-term heavy smoking on task-independent baseline brain activity are still unknown. Here, we used a regional homogeneity (ReHo) method combined with functional magnetic resonance imaging (fMRI) to investigate spontaneous neural activity in the resting state in heavy smokers. Compared with controls, heavy smokers exhibited decreased ReHo in prefrontal regions, as well as increased ReHo in insula and posterior cingulate cortex. Our study may better our understanding of the neurobiological consequences of smoking.
- [Show abstract] [Hide abstract] ABSTRACT: Recent studies suggest that internet addiction disorder (IAD) is associated with structural abnormalities in brain gray matter. However, few studies have investigated the effects of internet addiction on the microstructural integrity of major neuronal fiber pathways, and almost no studies have assessed the microstructural changes with the duration of internet addiction. We investigated the morphology of the brain in adolescents with IAD (N = 18) using an optimized voxel-based morphometry (VBM) technique, and studied the white matter fractional anisotropy (FA) changes using the diffusion tensor imaging (DTI) method, linking these brain structural measures to the duration of IAD. We provided evidences demonstrating the multiple structural changes of the brain in IAD subjects. VBM results indicated the decreased gray matter volume in the bilateral dorsolateral prefrontal cortex (DLPFC), the supplementary motor area (SMA), the orbitofrontal cortex (OFC), the cerebellum and the left rostral ACC (rACC). DTI analysis revealed the enhanced FA value of the left posterior limb of the internal capsule (PLIC) and reduced FA value in the white matter within the right parahippocampal gyrus (PHG). Gray matter volumes of the DLPFC, rACC, SMA, and white matter FA changes of the PLIC were significantly correlated with the duration of internet addiction in the adolescents with IAD. Our results suggested that long-term internet addiction would result in brain structural alterations, which probably contributed to chronic dysfunction in subjects with IAD. The current study may shed further light on the potential brain effects of IAD.
- [Show abstract] [Hide abstract] ABSTRACT: Previous functional imaging studies on heroin addicts have focused on abnormal brain functions based on specific tasks, while few fMRI studies concentrated on the resting-state abnormalities of heroin-dependent individuals. In the current study, we applied the pattern classification technique, which employs the feature extraction method of non-negative matrix factorization (NMF) and a support vector machine (SVM) classifier. Its main purpose was to characterize the discrepancy in activation patterns between heroin-dependent individuals and healthy subjects during the resting state. The results displayed a high accuracy in the activation pattern differences of the two groups, which included the orbitofrontal cortex (OFC), cingulate gyrus, frontal and para-limbic regions such as the anterior cingulate cortex (ACC), hippocampal/parahippocampal region, amygdala, caudate, putamen, as well as the posterior insula and thalamus. These findings indicate that significant biomarkers exist among the network of circuits that are involved in drug abuse. The implications from our study may help explain the behavioral and neuropsychological deficits in heroin-dependent individuals and shed light on the mechanisms underlying heroin addiction.
- [Show abstract] [Hide abstract] ABSTRACT: Drug addiction is a process associated with synaptic plasticity in which a drug of abuse affects the midbrain limbic system. Previous studies have indicated that drug abuse can be inhibited by disrupting the reconsolidation of a drug-related memory. Nuclear factor-κB (NF-κB) plays an important role in modulating different stages of memory, including reconsolidation, but its role in the reconsolidation of a reward memory has not been investigated. The aim of the present study was to examine the role of NF-κB in drug-related memory reconsolidation. We found that rats acquired morphine-induced conditioned place preference, which was inhibited by the NF-κB inhibitor SN50 administered after reexposure to a previously morphine-paired chamber (i.e., a memory retrieval process). The disruptive effect of SN50 on reward memory reconsolidation was reversed by systemic injections of the histone deacetylase inhibitor sodium butyrate. These results indicate that SN50 disrupts morphine-related memory reconsolidation by inhibiting NF-κB, and this effect can be reversed by inhibiting histone acetylation.
- [Show abstract] [Hide abstract] ABSTRACT: Previous neuroimaging studies have demonstrated both structural and functional damages in heroin-dependent individuals. However, few studies investigated gray matter deficits and abnormal resting-state networks together in heroin-dependent individuals. In the present study, voxel-based morphometry (VBM) was used to identify brain regions with gray matter density reduction. Resting-state fMRI connectivity analysis was employed to assess potential functional abnormalities during resting-state. All clinical significances were investigated by examining their association with duration of heroin use. Compared with healthy subjects, heroin-dependent individuals showed significant reduction in gray matter density in the right dorsolateral prefrontal cortex (DLPFC) and a decrease in resting-state functional connectivity between the right DLPFC and left inferior parietal lobe (IPL). The gray matter density of the right DLPFC and its resting-state functional connectivity with the left IPL both showed significantly negative correlation with duration of heroin use, which were likely to be related to the functional impairments in decision-making and cognitive control exhibited by heroin-dependent individuals. Our findings demonstrated that long heroin dependence impairs the right DLPFC in heroin-dependent individuals, including structural deficits and resting-state functional impairments.
- [Show abstract] [Hide abstract] ABSTRACT: Recent functional neuroimaging studies have examined cognitive inhibitory control, decision-making and stress regulation in heroin addiction using a cue-reactivity paradigm. Few studies have considered impairments in heroin users from an integrated perspective for evaluation of their brain functions. We hypothesized that the brain regions that are dysregulated in the chronic heroin users during cue-reactivity studies may also show dysfunctional connectivity in memory, inhibition and motivation-related dysfunctions during a resting state free of cues. The present study used resting functional magnetic resonance imaging (fMRI) to compare the interaction of brain regions between 12 chronic heroin users and 12 controls by employing a novel graph theory analysis (GTA) method. As a data-driven approach, GTA has the advantage of evaluating the strength as well as the temporal and spatial patterns of interactions among the brain regions. Abnormal topological properties were explored in the brain of chronic heroin users, such as the dysfunctional connectivity in the prefrontal cortex, ACC, SMA, ventral striatum, insula, amygdala and hippocampus. Our results suggest that GTA is a useful tool in defining dysregulated neural networks even during rest. This dysfunctional brain connectivity may contribute to decrease self-control, impaired inhibitory function as well deficits in stress regulation in chronic heroin users.