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Opiate abstinents (Novelty (European cohort = more representative for…

- - - - Vulnerability and neuro-developmental risk markers
      - Severity of use :checkered_flag:
      - Abstinence :checkered_flag:
      - Scales
  - - - Acute craving
      - Stress sensitivity
      - Personality
      - Risk of relapse
      - Emotional state :checkered_flag:
    - - Executive function :checkered_flag:
      - Working memory :checkered_flag:
      - Response inhibition :checkered_flag:
      - Premorbid IQ
  - - - Evocative image task
      - Go-NoGo task
      - Monetary incentive delay task
  - - - Genotyping
      - Gene expression
    - - Breath alcohol
      - Urinary drug screen
      - Routine blood samples
      - Pregnancy test
      - Pre-MRI questionnaire
- - - - Threshold :question:
    - - For opiates :question:
      - For other drugs :question:
  - - - Total duration of exposure:question:
        
        Threshold :question:
      - Total quantity of exposure :question:
        
        Threshold :question:
    - - Threshold :question:
    - - What kind of substitution :question:
  - - - Opiates need to be primary drug of use :question:
      - Threshold :question:
    - - Overlap exclusion :question:
      - Overlap exclusion threshold :question:
  - - - YES
        
        Proceed with cohort
        
        Enough subjects for relapse comparison :question: (15 vs. 15)
        
        NO :check:
        
        Move on and do more correlations
        
        YES
        
        Proceed
      - NO
        
        Consider reverting to poly-drug group
    - - 2:1 :question:
- - - - = looking at anomalies in the opiate abstinent brain
    - - = looking at anomalies in the opiate relapsing brain
  - - - Which resting state network ?
        
        Default mode network ? :check:
        
        :red_cross: Zhai et al. 2015 : 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 β-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 theβ-andδ-networks is balanced, and theδ-network competitively controls impulsivity. However, in abstinent heroin-dependent subjects, the link is imbalanced, with strongerβ-network connectivity and weakerδ-network connectivity. The imbalanced link is associated with impulsivity ,indicating that theβ-andδ-networks may mutually reinforce eachother in abstinent heroin-dependent subjects.
        These findings of an aberrant link between theβ-andδ-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.
        :red_cross:
        
        Basal ganglia network :lock:
        
        Executive control network :lock:
        
        Auditory network :check:
    - - What ROIs ?
        
        Maybe IF TIME :
        
        Within DMN depending on ICA
        
        Within basal ganglia network depending on ICA
        
        Executive control network depending on ICA
    - - If time : basal ganglia network :lock:
      - If time : executive control network :lock:
      - DMN
  - - - Positive ?
        
        Anxiety score STAI :check:
        
        State :question:
        
        Trait :question:
        
        Exposure :check:
        
        Create another variable combining : :red_cross:
        
        Total amount of use
        
        Route of intake (modulate with injection)
        
        Total duration of use
        
        Exposure variable :check:
        
        Depression score BDI-II :check:
        
        Affect :question:
        
        Total :question:
        
        Cogn :question:
      - Negative ?
        
        Months abstinent from opiates :check:
      - Other variables ? :question:
- - - - Looking at baseline acquired resting state scans
        
        on brain function and structure
        
        in comparison with matched healthy controls
        
        The effects of opioid dependence
  - - - DMN
      - If time :
        
        Basal ganglia network
        
        Executive control network
- - - - Resting state
        
        Yuan et al. 2010 : a decrease in resting-state functional connectivity between the right DLPFC and left inferior parietal lobe (IPL). 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.
        
        Eleven abstinent heroin-dependent males (right-handed, age 37.2 ± 7.3 years, range 25–47 years) were enrolled from a local methadone replacement therapy center. To avoid the confounding from co-morbidity of drug use, we carefully selected participants who were not dependent on other psychoactive drugs and reported no history of use of these drugs, except heroin and nicotine.
        
        We chose the right dorsolateral prefrontal cortex (DLPFC) as the “seeding” region for the functional connectivity analysis, because (1) VBM regression analysis showed that the gray matter density in the right DLPFC had significant negative correlation with the duration of heroin use; (2) a previous study revealed functional impairment of the DLPFC in heroin-dependent individuals [24].
        
        Yuan et al. 2010 : We observed that the default mode network (DMN) and rostral anterior cingulate cortex (rACC) network were changed in heroin-dependent individuals and these changes negatively correlated with duration of heroin use.Compared with healthy subjects, heroin-dependent individuals showed significantly reduced functional connectivity between PCC/Precuneus and right cerebellum (p < 0.05, corrected). In addition, the functional connectivity between PCC/Precuneus and right cerebellum during resting-state was negatively correlated with duration of heroin use in heroin-dependent individuals (Fig. 2). Heroin-dependent individuals showed significantly reduced functional connectivity between rACC and other regions, including left OFC, DLPFC and right middle temporal lobe (p < 0.05, corrected). Negative correlation was observed between these functional connectivity alterations and duration of heroin use in heroin-dependent individuals (Fig. 3).
        
        11 abstinent male heroin-dependent patients (right-handed, age 37.2 ± 7.3 years, range 25–47 years) were enrolled from a local methadone replacement therapy center. Exclusion criteria included psychiatric, neurological, and medical disorders requiring immediate treatment; additional current substance abuse/dependence diagnosis; and contraindications to scanning.
        
        We first applied DCT to explore the spatial distribution of low frequency BOLD oscillations in resting-state in heroin-dependent individuals and healthy subjects. Consistent with previous studies [4,15], we found a prominent presence of fluctuations in several brain regions, including PCC/Precuneus and rACC, in healthy subjects (Fig. 1). The heroin-dependent individuals DCT map was similar to healthy subjects. However, previous heroin studies had found structural changes and functional impairments in heroin-dependent individuals [6,13,14,16,17,25,26], we continued to study the temporal characteristics of brain regions with similar spatial patterns derived from DCT conjunction analysis. Fransson andMarrelec [5] found that the PCC/Precuneus was the only region that directly interacts with virtually all other regions in the DMN, using partial correlation analysis. They suggested that the PCC/Precuneus play a pivotal role in the DMN. In the present study, we chose the PCC/Precuneus as first ROI to detect PCC/Precuneus ntework (i.e. DMN) changes in heroin-dependent individuals. Recent neuroimaging studies have disclosed deactivation of the rACC in a GO/NOGO task in heroin-dependent individuals [1,6], indicating rACC’s essential role in response inhibition and inhibitory control [13]. In addition, emotional stress is revealed to contribute to drug use and relapse [19,21]. The exposure to stress was found to aggravate drug craving and relapse [2,20], which centrally involves rACC [13]. Therefore, the overlapping rACC in DCT conjunction analysis was identified as the second ROI.
        
        Yuan et al. 2010 : Our results demonstrated that compared with the control group, D were higher in the OFC, dorsolateral prefrontal cortex (DLPFC), rostral ACC (rACC), precuneus, parahippocampal gyrus, putamen and cerebellum bilaterally; the inferior frontal cortex, medial prefrontal cortex (MPFC), caudate, thalamus, and posterior cingulate cortex (PCC) in the left cerebrum; and finally, the right middle temporal gyrus in heroin-dependent patients (Fig. 1). The correlation analysis showed that the duration of heroin use was positively correlated with the D of the right parahippocampal gyrus, left putamen and bilateral cerebellum, but negatively correlated with the parameter L in the same regions (p < 0.05) (Fig. 2).
        
        11 abstinent heroin-dependent patients (right-handed males, age 37.2 ± 7.3 years, range 25–47 years) were enrolled from a local methadone replacement therapy center. Exclusion criteria included psychiatric, neurological, and medical disorders requiring immediate treatment; additional current substance abuse/dependence diagnosis; and contraindications to being scanned.
        
        A key issue in characterizing the brain topological network is the construction of the functional connection matrix. For comprehensively characterizing the topological properties of brain networks, we down-sampled the whole brain to 6 mm isotropic voxels and obtained 3446 regions of interest (ROI). To systematically investigate abnormal resting-state characteristics during the resting-state in heroin-dependent individuals, a novel approach to analyze complex systems, defined as the graph theory analysis (GTA), was applied to detect a sophisticated brain functional connection during resting-state within the heroin-dependent group and the control group, which thoroughly assesses the topological properties of networks by evaluating the strength, temporal and spatial patterns of interactions in the brain and is suitable to detect disruption in diseases-related networks [3,19,20]. To identify the relationship between chronic heroin use and features of the resting network, correlation analyses between statistical parameters (the degree: D and shortest absolute path length: L) and duration of heroin use were further carried out in heroin-dependent individuals.
        
        Ma et al. 2009 : Compared with controls, chronic heroin users showed increased functional connectivity between nucleus accumbens and ventral/rostral anterior cingulate cortex (ACC), between nucleus accumbens and orbital frontal cortex (OFC), and between amygdala and OFC and reduced functional connectivity between prefrontal cortex and OFC and between prefrontal cortex and ACC. Compared to controls, heroin users showed significantly (pb0.05, corrected) stronger functional connectivity between NAc and ventral/rostral ACC, between NAc and medial OFC, between amygdala and lateral OFC, between lateral OFC and medial OFC, and within medial OFC. On the other hand, compared to controls, heroin users exhibited significantly weaker functional connectivity between lateral OFC and medial, dorsolateral PFC, within lateral OFC, between dorsal ACC and dorsolateral prefrontal cortex (PFC), between dorsal ACC and ventral/rostral ACC, and between OFC and some frontal and parietal regions.
        
        14 chronic heroin users male only (HU, heroin using (from the time of their initial heroin use until the time of scanning) for 7.11± 2.82 years, range from 2 to 10 years) and 13 non-addicted controls (CN), participated in this study. All HU were recruited from Anhui Detoxification and Rehabilitation Center. According to an interview conducted by a clinical psychologist, all of the patients had never used any other types of illicit drugs.
        
        Four interdependent and overlapping circuits (Baler and Volkow, 2006): (i) reward, involving the nucleus accumbens and ventral pallidum; (ii) memory and learning, including the amygdala and hippocampus; (iii) cognitive control, located in the prefrontal cortex and dorsal anterior cingulate cortex; and (iv) motivation and/or drive and salience evaluation, located in the orbital frontal cortex. In addition, amygdala and ventral/rostral anterior cingulate cortex (including subgenual area), regions that are associated with craving and emotional regulation, are also likely to affect the reactivity of the above circuits and parts of this network. Ten brain regions, five in each hemisphere, were selected as seed regions of interest (seed ROIs) in this study (Fig. 1, Table 1). These ROIs were bilateral nucleus accumbens (NAc), amygdala (Amy), dorsal anterior cingulate cortex (Brodmann area (BA) 24/32), and orbital frontal cortex (OFC, including the lateral areas, BA 11/47, and the medial areas, BA 11/12).
        
        Liu et al. 2009 : Dysfunctional integrations occur in the brains of heroin-addicted individuals during the resting state. Dysregulation of these brain regions may reveal dysfunctional connectivity in the OFC and dorsolateral PFC in chronic heroin users. Compared with the non-drug users’ network, the ACC and SMA also showed irregular connectivities in the heroin-addicted group (Fig. 2). The present results also showed that the caudate, putamen, and pallidum had dysregulated functional connectivity in the heroin-addicted network compared with non-drug users. Interestingly, we also found a significantly degree of the insula in chronic heroin addicts network (Fig. 2). Based on our present observations, the amygdala and hippocampus were significant in degree comparisons (Fig. 2). Dysfunction of these regions in chronic heroin users during the resting state was accompanied by working memory-related activities.
        
        Xie et al. 2011 : 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
        
        We test the hypothesis that 1) The altered iAFC network pattern is associated with impulsive behavior, as measured by the Barratt Impulsiveness Scale (BIS, version 11) [27]; 2) The constructs of the impulsivity-associated network in abstinent heroin dependent (HD) subjects are different in comparison with those of cognitively normal (CN) subjects.
        
        22 abstinent heroin subjects and 15 control subjects for the final data analysis. All participants were male, right-handed and well-matched for age and years of education. Inclusion and exclusion criteria for heroin abusers and control subjects were described previously [8 -> no psychotropic agent use in the 3 months prior to admission to the study].
        
        Xie et al. 2014 : The underlying duality of the β-δ discounting networks that jointly influence valuation is impaired to a pathogenic state in abstinent heroin dependents. The imbalanced functional link between the β-δ networks for valuation may orchestrate the irrational choice in drug addiction.
        
        We selected the nucleus accumbens (NAc) region as a connective node or a “seed” region to link between the β- and δ-networks because the NAc plays an important role in drug addiction.
        
        Thirty-seven male, right-handed volunteers were recruited (22 heroin-dependent (HD) subjects and 15 nondrug users as control [CN] subjects). The characterization of the study subjects, inclusion and exclusion criteria, imaging data preprocessing and seed-based postprocessing procedures have been previously published (same as Xie 2011).
        
        Liu et al. 2011 : Comparing NDUs’ brain activity to that of CHUs, the intensity of functional connectivity of the medial frontal gyrus (meFG) in patients’ resting state networks was prominently greater and positively correlated with the same region’s neural activity in the heroin-related task; decreased functional connectivity intensity of the anterior cingulate cortex (ACC) in CHUs at rest was associated with more drugrelated cue-induced craving activities.
        
        Sixteen abstinent heroin-dependent males (right-handed, age 36.767.1 years, range 25–47 years) were recruited from a local methadone replacement therapy center. Exclusion criteria included psychiatric, neurological, and medical disorders requiring immediate treatment; additional current substance abuse/dependence diagnosis; and contraindications to being scanned.
        
        Within each sphere, the voxels located in the white matter and ventricles were removed to ensure the integrity of its structure and function. In this way, we could gain several regions of interest (ROIs). Isolated voxels showing significant regional differences in degree were excluded from the final ROIs. We considered these ROIs as network nodes and created fully connected, weighted, region-based networks for the CHUs’ and NDUs’ resting datasets. Based on each nodal degree, we performed a two-sample twotailed t-test to determine if the degree of the brain voxels was significantly different between the CHUs’ and NDUs’ resting networks (p,0.05, corrected). In order to avoid local correlations, we chose abnormal brain regions as the ROIs from the voxel-based network analysis to reconstruct the resting network for a region-based network analysis.
      - fMRI
        
        Fu et al. 2008 : methodology - there were 30 right-handed abstinent male heroin-dependent patients (AHD, mean age = 33.39 ± 5.98 years, range 24–44 years), who were recruited as inpatient while undergoing abstinence treatment at the AnKang hospital (Beijing, China), and 18 right-handed healthy male individuals (HC, mean age = 29.59 ± 6.94 years, range 23–44 years) recruited from the local community. All potential volunteers had a minimum of a nine-grade education and two groups were matched in terms of age, education and geographic location. The purpose of the experiment was explained to all subjects and their written informed consents were obtained. Eligibility criteria for AHD volunteers included: (1) meeting DSM-IV criteria for heroin dependence. Aside from heroin addiction, occasional diazepam and tramadol use, and regular use of cigarettes, the heroin dependent subjects denied any psychotropic agent use in the 3months prior to admission to the study; (2) at least 4 weeks since the last heroin use; (3) negative test for the presence of morphine in urine-analysis (reagent box produced by China Carrie City International Engineering Co.) and presence of human HIV in blood test; (4) normal intelligence as estimated by JC Raven progressive test [25]; (5) self-reported history of habitual heroin use for at least 2 years. Among the 30 patients, 10 subjects used heroin by ‘chasing the dragon’, 15 subjects injected themselves and the rest used both forms. The patients had a prior mean dosage per day of 0.69 g (S.D. = 0.54, range 0.2–2 g), mean abstinence from heroin of 7.64 weeks (S.D. = 2.16, range 4–11 weeks) and mean heroin dependent history of 6.25 years (S.D. = 3.53, range 2–15 years). The HC were only allowed occasional social use of alcohol and cigarettes, and they reported no use of psychoactive substances during the 72 h before the fMRI scan. None of the subjects were taking prescription drugs that affected the central nervous system, had a history of neurological illness or injury, or had a history of psychiatric illness or abnormalities demonstrated by an anatomical MRI.
      - Review
        
        Moningka et al. 2018 : Findings from resting-state studies generally support the hypothesis of altered DMN engagement among individuals with OUD, although the direction of these alterations has not been consistent across studies. As noted above, the identified resting state studies included a large number of methodological limitations, making interpretation of findings across studies problematic. In particular, given the variety of analysis methods employed (e.g., ALFF, ICA), the virtual absence of whole-brain analyses, and the relatively short durations of image acquisitions (e.g., ~5 min), collective findings from extant resting state analyses should be interpreted with caution. Thus, both acquisition of more data (i.e., longer durations) per subject (to improve within-subject reliability) and harmonization of analysis approaches and data pooling across studies are strongly recommended as important future directions for resting-state work in OUD populations [105,106,107,108,109,110]. As resting state analyses are particularly sensitive to motion effects, future studies should also incorporate more sophisticated motion correction techniques [111, 112] and test for possible effects of between-group (i.e., patients vs. controls) differences in motion on connectivity patterns.
  - - - Investigators at the McLean Hospital site (one facility of the multi-site Clinical Trials Network study on treatment of prescription opioid dependence) screened 133 candidates during a 36-month period preceding this report (Fig. 1). From these 133 patients, 48 candidates were disqualified due to the presence of other psychiatric or medical conditions, thus yielding 85 patients who were enrolled in the Prescription Opioid Addiction Treatment Study at McLean Hospital. Ultimately, 10 [age: 29.4 8.9 years (mean SD); gender: seven males, three females] non-smoking prescription opioid-dependent patients, meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for dependence on opioids were enrolled into the imaging arm of the study (Fig. 1). These 10 patients were free from any other psychiatric disorders (determined by the Composite International Diagnostic Interview) or other medical conditions, including pain. It is noted that 2 of the 10 patients started using prescription opioids in order to treat pain and were prescribed opioids for approximately a 2-week period. However, the two patients continued to use prescription opioids despite no longer having pain. Individuals with dependence on prescription opioids and a concurrent chronic pain condition were excluded from participation in the study. We further excluded subjects who had used any potentially confounding medications or drugs within the previous 3 months.
      - In the present work, the a priori emphasis was given to a few clearly identifiable key anatomical structures mediating reward, motivation and interoceptive processing, including cortical (insula) and subcortical (amygdala and nucleus accumbens) structures (Carlezon and Thomas, 2009).