Granger causality reveals a dominant role of memory circuit in chronic opioid dependence

Resting‐state magnetic resonance imaging has uncovered abnormal functional connectivity in heroin‐dependent individuals (HDIs). However, it remains unclear how brain regions implicated in addictions are related in baseline state without conditioned cues in heroin dependent individuals during opioid maintenance treatment (HDIs‐OMT). Previous connectivity analysis assessed the strength of correlated activity between brain regions but lacked the ability to infer directional neural interactions. In the current study, we employed Granger causality analysis to investigate directional causal influences among the brain circuits in HDIs‐OMT and non‐opioid users. The results revealed a weaker effective connectivity between the caudate nucleus implicated in mediating the reward circuit and other brain regions and also a weaker connectivity between the anterior cingulate cortex and medial prefrontal cortex implicated in mediating inhibitory control. Conversely, HDIs‐OMT exhibited stronger effective connectivity between the hippocampus and amygdala implicated in mediating learning‐memory, and the anterior cingulate cortex involved in mediating inhibitory control while the putamen mediated learned habits, suggesting that the hippocampus and amygdala may propel the memory circuit to override the control circuit and drive the learned habit in HDIs‐OMT. Alterations in learning‐memory and inhibitory control may contribute jointly and form a basis for relapse risk even after a period of heroin abstinence. Sustained neural effect of opioid dependence on methadone maintenance including hyperactivation in the memory circuit and impairment in the control circuit support the role of the memory circuitry in relapse and may help redefine targets for treatment.

[1]  Ying-wei Qiu,et al.  Regional homogeneity changes in heroin-dependent individuals: resting-state functional MR imaging study. , 2011, Radiology.

[2]  Qiang Li,et al.  Predicting subsequent relapse by drug‐related cue‐induced brain activation in heroin addiction: an event‐related functional magnetic resonance imaging study , 2015, Addiction biology.

[3]  L. Yao,et al.  Causal Interactions in Attention Networks Predict Behavioral Performance , 2012, The Journal of Neuroscience.

[4]  Y. Zang,et al.  Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI , 2007, Brain and Development.

[5]  N. Volkow,et al.  Addiction: Beyond dopamine reward circuitry , 2011, Proceedings of the National Academy of Sciences.

[6]  E. Stamatakis,et al.  Neural Correlates of the Severity of Cocaine, Heroin, Alcohol, MDMA and Cannabis Use in Polysubstance Abusers: A Resting-PET Brain Metabolism Study , 2012, PloS one.

[7]  Rainer Goebel,et al.  Information-based functional brain mapping. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Yihong Yang,et al.  Evaluating the effective connectivity of resting state networks using conditional Granger causality , 2010, Biological Cybernetics.

[9]  M D Devous,et al.  Limbic responsiveness to procaine in cocaine-addicted subjects. , 2001, The American journal of psychiatry.

[10]  Mareike M. Menz,et al.  Lower ventral striatal activation during reward anticipation in adolescent smokers. , 2011, The American journal of psychiatry.

[11]  Gui-hua Jiang,et al.  Amplitude low-frequency oscillation abnormalities in the heroin users: A resting state fMRI study , 2011, NeuroImage.

[12]  A. Ishai,et al.  Distributed and Overlapping Representations of Faces and Objects in Ventral Temporal Cortex , 2001, Science.

[13]  Brian Knutson,et al.  Dysfunction of reward processing correlates with alcohol craving in detoxified alcoholics , 2007, NeuroImage.

[14]  J S Fowler,et al.  Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. , 2000, Cerebral cortex.

[15]  N. Rathod.  Society for the Study of Addiction , 1977 .

[16]  Xiaoping Hu,et al.  Thirsty heroin addicts show different fMRI activations when exposed to water-related and drug-related cues. , 2006, Drug and alcohol dependence.

[17]  David J. Nutt,et al.  Functional connectivity analysis of the neural circuits of opiate craving: “more” rather than “different”? , 2003, NeuroImage.

[18]  Tatia M.C. Lee,et al.  Neural activity associated with cognitive regulation in heroin users: A fMRI study , 2005, Neuroscience Letters.

[19]  M. Brammer,et al.  Abnormal brain activation during inhibition and error detection in medication-naive adolescents with ADHD. , 2005, The American journal of psychiatry.

[20]  N. Volkow,et al.  The addicted human brain: insights from imaging studies. , 2003, The Journal of clinical investigation.

[21]  Yongcong Shao,et al.  Identification of hyperactive intrinsic amygdala network connectivity associated with impulsivity in abstinent heroin addicts , 2011, Behavioural Brain Research.

[22]  C. Li,et al.  Inhibitory control and emotional stress regulation: Neuroimaging evidence for frontal–limbic dysfunction in psycho-stimulant addiction , 2008, Neuroscience & Biobehavioral Reviews.

[23]  K. Yuan,et al.  Craving correlates with mesolimbic responses to heroin-related cues in short-term abstinence from heroin: An event-related fMRI study , 2012, Brain Research.

[24]  E. Stein,et al.  Chronic Exposure to Nicotine Is Associated with Reduced Reward-Related Activity in the Striatum but not the Midbrain , 2012, Biological Psychiatry.

[25]  M. Ding,et al.  Granger causal influence predicts BOLD activity levels in the default mode network , 2011, Human brain mapping.

[26]  R. Goebel,et al.  Investigating directed influences between activated brain areas in a motor-response task using fMRI. , 2006, Magnetic resonance imaging.

[27]  Antoine Bechara,et al.  Decision-making and impulse control after frontal lobe injuries , 2005, Current opinion in neurology.

[28]  Matthijs G. Bossong,et al.  Delta 9-tetrahydrocannabinol induces dopamine release in the human striatum , 2008, NeuroImage.

[29]  Wei Wang,et al.  Interaction between Dysfunctional Connectivity at Rest and Heroin Cues-Induced Brain Responses in Male Abstinent Heroin-Dependent Individuals , 2011, PloS one.

[30]  Jimin Liang,et al.  Dysfunctional connectivity patterns in chronic heroin users: An fMRI study , 2009, Neuroscience Letters.

[31]  Hiroki M. Morimoto,et al.  Functional dissociation in right inferior frontal cortex during performance of go/no-go task. , 2009, Cerebral cortex.

[32]  T. Lundqvist,et al.  Imaging cognitive deficits in drug abuse. , 2010, Current topics in behavioral neurosciences.

[33]  J. P. Hamilton,et al.  Investigating neural primacy in Major Depressive Disorder: Multivariate granger causality analysis of resting-state fMRI time-series data , 2010, Molecular Psychiatry.

[34]  E. Stein,et al.  Cue-induced cocaine craving: neuroanatomical specificity for drug users and drug stimuli. , 2000, The American journal of psychiatry.

[35]  M. Paulus,et al.  Functional MRI of inhibitory processing in abstinent adolescent marijuana users , 2007, Psychopharmacology.

[36]  N M White,et al.  Addictive drugs as reinforcers: multiple partial actions on memory systems. , 1996, Addiction.

[37]  C. Schroeder,et al.  Neuronal Mechanisms of Cortical Alpha Oscillations in Awake-Behaving Macaques , 2008, The Journal of Neuroscience.

[38]  Nora D. Volkow,et al.  Gastric distention activates satiety circuitry in the human brain , 2008, NeuroImage.

[39]  D. Penetar,et al.  Response inhibition and psychomotor speed during methadone maintenance: impact of treatment duration, dose, and sleep deprivation. , 2012, Drug and alcohol dependence.

[40]  S. Hyman,et al.  Acute Effects of Cocaine on Human Brain Activity and Emotion , 1997, Neuron.

[41]  Dieter Vaitl,et al.  Neuroimaging of emotion: empirical effects of proportional global signal scaling in fMRI data analysis , 2005, NeuroImage.

[42]  Mingzhou Ding,et al.  The neurobiological drive for overeating implicated in Prader–Willi syndrome , 2015, Brain Research.

[43]  T L Faber,et al.  Neural activity related to drug craving in cocaine addiction. , 2001, Archives of general psychiatry.

[44]  Daniel Y. Kimberg,et al.  Neural correlates of cognitive efficiency , 2006, NeuroImage.

[45]  W. Schultz,et al.  Changes in reward‐induced brain activation in opiate addicts , 2001, The European journal of neuroscience.

[46]  R. Frances.  Is Decreased Prefrontal Cortical Sensitivity to Monetary Reward Associated With Impaired Motivation and Self-Control in Cocaine Addiction? , 2008 .

[47]  Dongqi Zhao,et al.  Opiate addiction in China: current situation and treatments. , 2006, Addiction.

[48]  Yong He,et al.  Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. , 2007, Brain & development.

[49]  N. Volkow,et al.  Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications , 2011, Nature Reviews Neuroscience.

[50]  Zheng Yang,et al.  Impaired response inhibition function in abstinent heroin dependents: An fMRI study , 2008, Neuroscience Letters.

[51]  C. Chen,et al.  A Memory Retrieval-Extinction Procedure to Prevent Drug Craving and Relapse , 2012, Science.

[52]  Jianfeng Feng,et al.  Componential Granger causality, and its application to identifying the source and mechanisms of the top–down biased activation that controls attention to affective vs sensory processing , 2012, NeuroImage.

[53]  D. Kupfer,et al.  Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria , 2001, Biological Psychiatry.

[54]  Rainer Goebel,et al.  Combining multivariate voxel selection and support vector machines for mapping and classification of fMRI spatial patterns , 2008, NeuroImage.

[55]  S. Bressler,et al.  Frequency decomposition of conditional Granger causality and application to multivariate neural field potential data , 2006, Journal of Neuroscience Methods.

[56]  J. Monterosso,et al.  Ventral Striatal Dopamine Release in Response to Smoking a Regular vs a Denicotinized Cigarette , 2009, Neuropsychopharmacology.

[57]  J S Fowler,et al.  Long‐Term frontal brain metabolic changes in cocaine abusers , 1992, Synapse.

[58]  Brian Knutson,et al.  Ventral Striatal Activation During Reward Anticipation Correlates with Impulsivity in Alcoholics , 2009, Biological Psychiatry.

[59]  C. Schroeder,et al.  Neuronal Mechanisms and Attentional Modulation of Corticothalamic Alpha Oscillations , 2011, The Journal of Neuroscience.

[60]  Chun-Ming Xie,et al.  Dynamic neural responses to cue‐reactivity paradigms in heroin‐dependent users: An fMRI study , 2009, Human brain mapping.

[61]  S. Bressler,et al.  Granger Causality: Basic Theory and Application to Neuroscience , 2006, q-bio/0608035.

[62]  Qiang Li,et al.  Altered Fronto-Striatal and Fronto-Cerebellar Circuits in Heroin-Dependent Individuals: A Resting-State fMRI Study , 2013, PloS one.

[63]  Qiang Li,et al.  Assessing Cue-Induced Brain Response as a Function of Abstinence Duration in Heroin-Dependent Individuals: An Event-Related fMRI Study , 2013, PloS one.

[64]  N. Volkow,et al.  Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. , 1999, The Journal of pharmacology and experimental therapeutics.

[65]  Mingzhou Ding,et al.  Is Granger Causality a Viable Technique for Analyzing fMRI Data? , 2013, PloS one.

[66]  J S Fowler,et al.  Changes in brain glucose metabolism in cocaine dependence and withdrawal. , 1991, The American journal of psychiatry.

[67]  Rainer Goebel,et al.  Mapping directed influence over the brain using Granger causality and fMRI , 2005, NeuroImage.

[68]  R. See,et al.  The neurocircuitry of addiction: an overview , 2008, British journal of pharmacology.

[69]  J. White,et al.  Patterns of symptom complaints in methadone maintenance patients. , 1997, Addiction.

[70]  B. Everitt,et al.  Behavioral and neural mechanisms of compulsive drug seeking. , 2005, European journal of pharmacology.

[71]  M. Kreek,et al.  Methadone‐Related Opioid Agonist Pharmacotherapy for Heroin Addiction: History, Recent Molecular and Neurochemical Research and Future in Mainstream Medicine , 2000, Annals of the New York Academy of Sciences.

[72]  V. Menon,et al.  A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks , 2008, Proceedings of the National Academy of Sciences.

[73]  John C Gore,et al.  Assessing functional connectivity in the human brain by fMRI. , 2007, Magnetic resonance imaging.

[74]  L. Yao,et al.  Top-Down Regulation of Default Mode Activity in Spatial Visual Attention , 2013, The Journal of Neuroscience.

[75]  T. Robbins,et al.  Neural systems of reinforcement for drug addiction: from actions to habits to compulsion , 2005, Nature Neuroscience.

[76]  M. D’Esposito,et al.  Empirical analyses of BOLD fMRI statistics. I. Spatially unsmoothed data collected under null-hypothesis conditions. , 1997, NeuroImage.

[77]  M. Corbetta,et al.  Top-Down Control of Human Visual Cortex by Frontal and Parietal Cortex in Anticipatory Visual Spatial Attention , 2008, The Journal of Neuroscience.

[78]  Jonathan Berger,et al.  Neural Dynamics of Event Segmentation in Music: Converging Evidence for Dissociable Ventral and Dorsal Networks , 2007, Neuron.

[79]  Kosha Ruparel,et al.  Acute effect of methadone maintenance dose on brain FMRI response to heroin-related cues. , 2008, The American journal of psychiatry.

[80]  Rajesh Kumar,et al.  A method for removal of global effects from fMRI time series , 2004, NeuroImage.

[81]  Gary F. Egan,et al.  Simulation of the Effects of Global Normalization Procedures in Functional MRI , 2002, NeuroImage.

[82]  Ning Ma,et al.  Addiction related alteration in resting-state brain connectivity , 2010, NeuroImage.

[83]  A. Dagher,et al.  Alcohol promotes dopamine release in the human nucleus accumbens , 2003, Synapse.

[84]  M. D’Esposito,et al.  The Variability of Human, BOLD Hemodynamic Responses , 1998, NeuroImage.

[85]  N. Volkow,et al.  The neural basis of addiction: a pathology of motivation and choice. , 2005, The American journal of psychiatry.

[86]  Sean M. Polyn,et al.  Beyond mind-reading: multi-voxel pattern analysis of fMRI data , 2006, Trends in Cognitive Sciences.

[87]  Rita Z. Goldstein,et al.  Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. , 2002, The American journal of psychiatry.

[88]  N. Volkow,et al.  Cocaine Cues and Dopamine in Dorsal Striatum: Mechanism of Craving in Cocaine Addiction , 2006, The Journal of Neuroscience.

[89]  Jie Tian,et al.  Distinct resting-state brain activities in heroin-dependent individuals , 2011, Brain Research.

[90]  Opiate , 2019, Springer Reference Medizin.

[91]  S. Bressler,et al.  Beta oscillations in a large-scale sensorimotor cortical network: directional influences revealed by Granger causality. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[92]  M. Schocke,et al.  A widespread distinct pattern of cerebral atrophy in patients with alcohol addiction revealed by voxel-based morphometry , 2006, Journal of Neurology, Neurosurgery & Psychiatry.