Circadian misalignment leads to changes in cortisol rhythms, blood biochemical variables and serum miRNA profiles.

The circadian clock plays a critical role in synchronizing the inner molecular, metabolic and physiological processes to environmental cues that cycle with a period of 24 h. Non-24 h and shift schedules are commonly used in maritime operations, and both of which can disturb circadian rhythms. In this study, we first conducted an experiment in which the volunteers followed a 3-d rotary schedule with consecutive shift in sleep time (rotatory schedule), and analyzed the changes in salivary cortisol rhythms and blood variables. Next we conducted another experiment in which the volunteers followed an 8 h-on and 4-h off schedule (non-24-h schedule) to compare the changes in blood/serum variables. The rotatory schedule led to elevated levels of serum cortisol during the early stage, and the phase became delayed during the early and late stages. Interestingly, both of the schedules caused comprehensive changes in blood/serum biochemical variables and increased phosphate levels. Furthermore, transcriptomic analysis of the plasma miRNAs from the volunteers following the rotatory schedule identified a subset of serum miRNAs targeting genes involved in circadian rhythms, sleep homeostasis, phosphate transport and multiple important physiological processes. Overexpression of miRNAs targeting the phosphate transport associated genes, SLC20A1 and SLC20A2, showed altered expression due to rotary schedule resulted in attenuated cellular levels of phosphate, which might account for the changed levels in serum phosphate. These findings would further our understanding of the deleterious effects of shift schedules and help to optimize and enhance the performances and welfare of personnel working on similar schedules.

Abnormal gray matter volume and resting-state functional connectivity in former heroin-dependent individuals abstinent for multiple years.

Previous studies have suggested that heroin addiction is associated with structural and functional brain abnormalities. However, it is largely unknown whether these characteristics of brain abnormalities would be persistent or restored after long periods of abstinence. Considering the very high rates of relapse, we hypothesized that there may exist some latent neural vulnerabilities in abstinent heroin users. In this study, structural and resting-state functional magnetic resonance imaging data were collected from 30 former heroin-dependent (FHD) subjects who were drug free for more than 3 years and 30 non-addicted control (CN) volunteers. Voxel-based morphometry was used to identify possible gray matter volume differences between the FHD and CN groups. Alterations in resting-state functional connectivity in FHD were examined using brain areas with gray matter deficits as seed regions. Significantly reduced gray matter volume was observed in FHD in an area surrounding the parieto-occipital sulcus, which included the precuneus and cuneus. Functional connectivity analyses revealed that the FHD subjects showed reduced positive correlation within the default mode network and visual network and decreased negative correlation between the default mode network, visual network and task positive network. Moreover, the altered functional connectivity was correlated with self-reported impulsivity scores in the FHD subjects. Our findings suggest that disruption of large-scale brain systems is present in former heroin users even after multi-year abstinence, which could serve as system-level neural underpinnings for behavioral dysfunctions associated with addiction.

Abnormal resting-state functional connectivity of the nucleus accumbens in multi-year abstinent heroin addicts.

Functional neuroimaging studies suggest that abnormal brain functional connectivity may be the neural underpinning of addiction to illicit drugs and of relapse after successful cessation therapy. Aberrant brain networks have been demonstrated in addicted patients and in newly abstinent addicts. However, it is not known whether abnormal brain connectivity patterns persist after prolonged abstinence. In this cross-sectional study, whole-brain resting-state functional magnetic resonance images (8 min) were collected from 30 heroin-addicted individuals after a long period of abstinence (more than 3 years) and from 30 healthy controls. We first examined the group differences in the resting-state functional connectivity of the nucleus accumbens (NAc), a brain region implicated in relapse-related processes, including craving and reactivity to stress following acute and protracted withdrawal from heroin. We then examined the relation between the duration of abstinence and the altered NAc functional connectivity in the heroin group. We found that, compared with controls, heroin-dependent participants exhibited significantly greater functional connectivity between the right ventromedial prefrontal cortex and the NAc and weaker functional connectivity between the NAc and the left putamen, left precuneus, and supplementary motor area. However, with longer abstinence time, the strength of NAc functional connectivity with the left putamen increased. These results indicate that dysfunction of the NAc functional network is still present in long-term-abstinent heroin-dependent individuals.

Nature of functional links in valuation networks differentiates impulsive behaviors between abstinent heroin-dependent subjects and nondrug-using subjects.

Advanced neuroimaging studies have identified brain correlates of pathological impulsivity in a variety of neuropsychiatric disorders. However, whether and how these spatially separate and functionally integrated neural correlates collectively contribute to aberrant impulsive behaviors remains unclear. Building on recent progress in neuroeconomics toward determining a biological account of human behaviors, we employed resting-state functional MRI to characterize the nature of the links between these neural correlates and to investigate their impact on impulsivity. We demonstrated that through functional connectivity with the ventral medial prefrontal cortex, the δ-network (regions of the executive control system, such as the dorsolateral prefrontal cortex) and the ß-network (regions of the reward system involved in the mesocorticolimbic pathway), jointly influence impulsivity measured by the Barratt impulsiveness scale scores. In control nondrug-using subjects, the functional link between the ß- and δ-networks is balanced, and the δ-network competitively controls impulsivity. However, in abstinent heroin-dependent subjects, the link is imbalanced, with stronger ß-network connectivity and weaker δ-network connectivity. The imbalanced link is associated with impulsivity, indicating that the ß- and δ-networks may mutually reinforce each other in abstinent heroin-dependent subjects. These findings of an aberrant link between the ß- and δ-networks in abstinent heroin-dependent subjects may shed light on the mechanism of aberrant behaviors of drug addiction and may serve as an endophenotype to mark individual subjects' self-control capacity.

Altered intrinsic hippocmapus declarative memory network and its association with impulsivity in abstinent heroin dependent subjects.

Converging evidence suggests that addiction can be considered a disease of aberrant learning and memory with impulsive decision-making. In the past decades, numerous studies have demonstrated that drug addiction is involved in multiple memory systems such as classical conditioned drug memory, instrumental learning memory and the habitual learning memory. However, most of these studies have focused on the contributions of non-declarative memory, and declarative memory has largely been neglected in the research of addiction. Based on a recent finding that hippocampus, as a core functioning region of declarative memory, was proved biased the decision-making process based on past experiences by spreading associated reward values throughout memory. Our present study focused on the hippocampus. By utilizing seed-based network analysis on the resting-state functional MRI datasets with the seed hippocampus we tested how the intrinsic hippocampal memory network altered toward drug addiction, and examined how the functional connectivity strength within the altered hippocampal network correlated with behavioral index 'impulsivity'. Our results demonstrated that HD group showed enhanced coherence between hippocampus which represents declarative memory system and non-declarative reward-guided learning memory system, and also showed attenuated intrinsic functional link between hippocampus and top-down control system, compared to the CN group. This alteration was furthered found to have behavioral significance over the behavioral index 'impulsivity' measured with Barratt Impulsiveness Scale (BIS). These results provide insights into the mechanism of declarative memory underlying the impulsive behavior in drug addiction.

Identification of hyperactive intrinsic amygdala network connectivity associated with impulsivity in abstinent heroin addicts.

Impulsivity is a pathological hallmark of drug addiction. However, little is known about the neuropsychological underpinnings of this impaired impulsive control network on drug addiction. Twenty two abstinent heroin dependent (HD) subjects and 15 cognitively normal (CN) subjects participated in this study. Resting-state functional connectivity MRI was employed to measure abnormalities in the intrinsic amygdala functional connectivity (iAFC) network activity and the Barratt Impulsive Scale, 11th version was used to measure impulsivity. Linear regression analysis was applied to detect the neural constructs underlying impulsivity by correlating iAFC network activity with impulsive scores. In the HD group, higher impulsivity scores and significantly enhanced iAFC network activity were found, especially in bilateral thalamus, right insula, and inferior frontal gyrus. Markedly decreased anticorrelated iAFC network activity was seen in the left precuneus, and even switched to positive correlation pattern in right precuneus, relative to the CN group. The iAFC network strengths in the HD group were positively correlated with impulsivity in the right subcallosal gyrus, insula, thalamus and posterior cingulate cortex, and negatively correlated in left fusiform area. In the CN group, the left pre-somamotor area-amygdala connectivity was positively correlated, and right orbital frontal cortex-amygdala and precuneus-amygdala connectivity were negatively correlated with impulsivity scores. Our study demonstrates different constructs of the impulsive network in HD and CN subjects. Altered iAFC network connectivity in HD subjects may contribute to the loss of impulsive control. This further facilitates our understanding of the neural underpinnings of behavior dysfunction in addiction.

Dynamic neural responses to cue-reactivity paradigms in heroin-dependent users: an fMRI study.

Neuroimaging methods have been employed to study cue-reactivity-induced neural correlates in the human brain. However, very few studies have focused on characterizing the dynamic neural responses to the factorial interactions between the cues and the subjects. Fifteen right-handed heroin-dependent subjects and 12 age-matched nondrug using subjects participated in this study. Cue-reactivity paradigms were employed, while changes in blood oxygenation level-dependent (BOLD) signals were acquired by functional MRI (fMRI). The fMRI datasets were analyzed with AFNI software and repeated two-way ANOVA was employed for factorial analyses. Neural correlates of factorial interactions between cue-factor and subject-factor were identified in the regions of the ventral tegmental area (VTA), the left and right amygdala, the left and right fusiform cortex, and the precuneus in the mesocorticolimbic system, and in the superior frontal, dorsal lateral prefrontal, and orbitofrontal cortices in the prefrontal cortex system. The neural response patterns in the prefrontal systems are dynamic: decreased response to neutral-cues and increased response to heroin-cues. Further, heroin-cue-induced neural responses within the subregions in the PFC system are significantly intercorrelated. In conclusion, the cue-reactivity paradigms significantly activated the dynamic neural activations in the prefrontal system. It is suggested that the dynamic response patterns in the PFC system characterize the impaired brain control functions in heroin-dependent subjects.

Medication of l-tetrahydropalmatine significantly ameliorates opiate craving and increases the abstinence rate in heroin users: a pilot study.

AIM: Drug addiction is a chronic brain disease with constant relapse requiring long-term treatment. New pharmacological strategies focus on the development of an effective antirelapse drug. This study examines the effects of levotetrahydropalmatine (l-THP) on reducing heroin craving and increasing the abstinence rate among heroin-dependent patients. METHODS: In total, 120 heroin-dependent patients participated in the randomized, double-blinded, and placebocontrolled study using l-THP treatment. The participants remained in a ward during a 4-week period of l-THP treatment, followed by 4 weeks of observation after treatment. The patients were followed for 3 months after discharge. Outcome measures are the measured severity of the protracted abstinence withdrawal syndrome (PAWS) and the abstinence rate. RESULTS: Four weeks of l-THP treatment significantly ameliorated the severity of PAWS, specifically, somatic syndrome, mood states, insomnia, and drug craving, in comparison to the placebo group. Based on the 3 month follow-up observation, participants who survived the initial 2 weeks of l-THP medication and remained in the trial program had a significantly higher abstinence rate of 47.8% (95% confidence interval [CI]: 33%- 67%) than the 15.2% in the placebo group (95% CI: 7%-25%), according to a log- rank test (P<0.0005). CONCLUSION: l-THP significantly ameliorated PAWS, especially reducing drug craving. Furthermore, it increased the abstinence rate among heroin users. These results support the potential use of l-THP for the treatment of heroin addiction.