The development of functional imaging techniques such as Positron Emission Tomography and functional Magnetic Resonance Imaging , has allowed the high-resolution mapping of the brain in-vivo, in people with SUD. This body of work has provided increasing evidence that SUD is associated with alterations in the anatomy and the functional brain pathways ascribed to reward, learning, and EF. Importantly, emerging evidence suggests that neuroimaging versus subjective measures in SUD may predict with greater precision addiction-relevant cognitive processes and treatment outcomes.Functional imaging techniques allowed exploration of whether brain dysfunction is implicated in SUD in humans. These create images of brain function by relying on proxies, including metabolic properties of the brain. The application of functional imaging has been crucial to reveal the impact of SUD on human brain function in areas ascribed to cognitive processes and positive and negative emotions .PET imaging relies on the movement of injected radioactive material to identify whether the metabolic activity of brain regions is related to cognitive functions . PET’s invasiveness and high financial costs have resulted in a limited number of studies using it, and its low temporal and spatial resolutions prevented the identification of subtle brain activity alterations in SUD samples . The development of fMRI provided a way to overcome these limitations. Unlike PET, fMRI is non-invasive, promoting feasibility in unpacking the neural correlates of SUD . Specifically, fMRI generates information about brain activity by exploiting the magnetic properties of oxygenated and deoxygenated blood . Further, fMRI provides information on the brain’s functional activity with higher temporal and spatial resolutions than those of PET, i.e., within seconds and millimeters, respectively . These methodological advantages have allowed many studies to map the neural pathways implicated in SUD,hydroponics flood table while providing information on brain function within a high spatial and temporal resolution.

However, a well-described limitation of fMRI analyses is the difficulty to control for multiple tests and related false positive errors . The neuroimaging community has started to implement several strategies to address this limitation , but the use of liberal thresholds has probably inflated false positive rates in earlier studies. Using multi-modal imaging techniques is warranted to further unpack the neural mechanisms of SUD and abstinence. For instance, integrating structural MRIdata with Magnetic Resonance Spectroscopy Imaging, an MRI imaging technique that allows investigation of metabolites in the brain, may provide insight into the biochemical changes associated with volumetric alterations in SUD. Further, conducting brief, repeated task-free fMRI studies during treatment/abstinence could provide a better understanding of the impact of clinical changes on intrinsic brain architecture. An advantage of resting-state functional imaging data is the possibility of investigating patterns of brain function without restrictive “forces” on brain function placed by a specific task. Finally, studying SUD with modalities such as Diffusion Tensor Imaging may reveal alteration in white matter pathways that connect brain regions that are volumetrically altered. This approach may inform the pathophysiology of volumetric alterations in SUD-relevant brain circuits.Table 1 overviews key neurobehavioral pathways implicated by prominent neuroscientific theories of addiction and a growing body of work. These include neurobehavioral systems implicated in positive valence, negative valence, interoception, and EF . Abstinence may recover and mitigate such brain alterations and related cognitive functions, e.g., increase in response inhibition capacity, lower stress and drug reactivity, learning new responses to drugs and related stimuli. This notion is yet to be tested using robust neuroimaging methods that, in conjunction with treatment-relevant clinical and cognitive measures, measure and track the integrity of specific neural pathways during abstinence . The neurobiology of abstinence has been posited to entail two core processes . The first is the restored integrity of brain function, as drug levels in the central nervous system and bloodstream clear out with abstinence. The second is the retraining of neural pathways implicated in cognitive changes that enable abstinence. These include awareness/monitoring of internal psychological/physiological states , withdrawal and craving ; EF ; monitoring conflict between short-term goals versus long-term goals ; motivation to use drugs ; and learning new responses to drug-related and other stimuli.

Most neuroimaging studies to date have mapped dysfunctional neural pathways in SUD. There is a significant lack of work that tracks abstinence-related brain changes over time. This evidence gap prevents neuroimaging studies from informing the identification of treatment targets and clinical practice. It is unclear if abstinence leads to recovery of SUD-related brain dysfunction ,engages additional pathways implicated in abstinence-related cognitive, clinical, and behavioral changes, and is predicted by specific brain measures assessed pre-treatment. Emerging evidence from standard behaviora land pharmacological treatments that directly affect the central nervous system provides preliminary support for these notions, as reviewed in detail in previous work [see ]. This section provides an overview of early neuroimaging evidence for brain changes related to abstinence and novel interventions .Abstinence may “reverse” brain dysfunction and volume loss associated with SUD. Studies have observed increased or normalized volumes in global and prefrontal brain regions related to abstinence in people with alcohol use disorder and cocaine and opiate use disorders . PET and DTI studies of alcohol and cocaine users showed recovery of brain dysfunction and white matter integrity following heterogeneous abstinence durations, e.g., from about a month , to several months and several years . Results from fMRI tasks of response inhibition in abstinent users also showed that reduced brain function typically associated with drug use, was “restored” and increased in prefrontal and cerebellar pathways in former versus current cigarette smokers, and in former cannabis usersversus non-users . Emergingevidence showed that abstinence duration was associated with improved integrity of cortical and prefrontal pathways . Additionally, abstinence related neuroadaptations have been associated with substance use levels [e.g., cocaine dose, and performance was improved during cognitive tasks relevant to addiction e.g., processing speed, memory, EF-shifting. Thus, abstinence-related brain changes may in part drive treatment relevant outcomes.

Several neuroimaging studies have examined whether brain integrity in SUD predicts abstinence, with promising results. Studies of brain structure in people with nicotine and alcohol use disorders reported that increased volume and white matter integrity in prefrontal regions, followed by parietal and subcortical areas, most consistently segregated abstainers versus relapsers . Studies have examined brain function using fMRI tasks that engage cognitive domains relevant to treatment response. These studies provided evidence that the function of fronto-striatal regions in particular, followed by other regions discriminated responders versus nonresponders, relapsers versus non-relapsers in cigarette smokers and people with methamphetamine, cocaine and alcohol use disorders . Also,hydroponic stands the activity of fronto-striatal pathways have been shown to predict alcohol dosage at 6 month follow-up . Studies that used other functional imaging techniques such as spectroscopy and PET imaging consistently reported that frontal blood flow and metabolites and the density of dopamine receptors predicted treatment outcome in alcohol users and relapse in methamphetamine users .Novel training strategies that target core cognitive dysfunctions in SUD have shown promise to restore cognitive alterations and help maintain abstinence . One example includes cognitive bias modification strategies that reduce attentional biases towards substance related cues [see study in tobacco smokers ]. Such strategies may target top-down and bottom-up brain pathway simplicated in addiction . These include increasing the activity of top-down EF regions that enhance inhibitory control and behavioral monitoring , and decreasing reactivity of bottom-up pathways implicated in reactivity to drug stimuli, and craving . Early neuroimaging evidence has examined the neuroadaptations that occur pre-to-post-cognitive bias modification training. These findings are revised and discussed in the COGNITIVE TRAINING AND REMEDIATION section below. There is a paucity of neuroimaging research on other cognitive training and remediation approaches, despite promising evidence of neuroplasticity-related changes after cognitive remediation in brain injury .Mindfulness-based interventions are being increasingly used for the treatment of SUD . Although mindfulness does not use standard cognitive training/remediation approaches, it has shown to improve SUD-relevant cognitive processes such as attention and EFas well as substance use outcomes. Mindfulness-based interventionseng age two key cognitive processes focused attention, which consists of paying attention to a specific stimulus while letting go of distractions and open monitoring, which refers to the being aware of internal and external stimuli with a non-judgmental attitude and acceptance. The effectiveness of mindfulness-based interventions has been ascribed to improved function of prefrontal, parietal, and insula regions that are implicated in EF and autonomic regulation , and down-regulation of reactivity in striatal/amygdala regions implicated in reward, stress, and habitual substance use . Only a handful of neuroimaging studies have examined brain changes that occur with mindfulness-based interventions in SUD. This includes a fMRI study in tobacco smokers that showed a 10-session mindfulness-oriented recovery enhancement versus placebo intervention, decreased activity of the ventral striatum, and medial prefrontal regions during a craving task and an emotion regulation task . Most evidence on mindfulness and SUD consists of behavioral studies that showed robust effects on cognition, substance use, and craving. Given the widespread use of mindfulness-based interventions in clinical settings, we advocate the conduct of active placebo-controlled neuroimaging studies that map the neurobiology of mindfulness in SUD.Overall, there is a paucity of neuroimaging studies of treatment and abstinence in SUD.

The study methods are very heterogeneous which precludes their systematic integration. First, there was significant heterogeneity in treatments, with distinct durations and hypothesized neurobehavioral and pharmacological mechanisms of action, and distinct treatment responses across different individuals, SUD and related psychiatric comorbidities. Second, control groups varied substantially and brain changes related to abstinence were compared to different types of controls . Third, repeated measures study designs had varying data testing points that precluded the integration of the study findings and mapping treatment-related, trajectories of brain changes with abstinence/recovery. More systematic evidence is needed to provide sufficient power to measure brain pathways relevant to treatment response and to inform clinically-relevant treatment endpoints. In order to address this gap, the ISAM-NIG Neuroimaging stream recommends the conduct of harmonized, multi-site, neuroimaging studies with systematic testing protocols of relevance for clinical practice. It is hoped that the ISAM-NIG Neuroimaging approach will generate results that can be readily integrated and that increase the power to detect abstinence-related neuroadaptations. On one hand, the integration of neuroimaging testing into clinical practice can be challenging. MRI scanners are extremely expensive to buy, setup, and run safely, and the acquisition of high-quality brain images requires extensive specialized technical expertise. On the other hand, the availability of MRI scans in many hospitals, universities, and medical institutions, may provide ideal settings to integrate neuroimaging and clinical expertise. MRI scans can be feasible in that they are non-invasive, safe, and can be relatively quick . Outstanding challenges to address remain funding sources, the lack of integration in the theoretical frameworks between basic research, clinical science, and clinical practice. Discipline-specific specialized language and practices can also create barriers. We advocate using team science to develop a harmonized interdisciplinary framework, so that all stakeholders, including clinicians, neuropsychologists, social workers and neuroscientists interact to inform commonly-agreed testing batteries and most profitable directions for future work. The present review has focused on neuroimaging data mainly acquired through fMRI, allowing for visualization of the brain networks involved in certain conditions . However, it should be noted that the coarse temporal resolution of such techniquesimpedes determination of the temporal activation sequence , allowing the specific brain activation patterns to be correlated with the various cognitive stages involved in the investigated processes [e.g., ]. Other tools, such as cognitive event related potentials in particular, might be more suitable for this purpose . Nowadays, different studies reveal that specific ERP components tagging specific cognitive functions may be used as neurophysiological biomarkers for addiction treatment outcome prediction . Such data may be of great value to clinicians for the identification of cognitive processes that should be rehabilitated on a patient-by-patient basis through cognitive training and/or brain stimulation. However, despite technical facilities , several decades of research, and clinical relevance, ERPs like other neuroimaging modalities have yet to be implemented in the clinical management of SUD.Despite recent advances in psychological and pharmacological interventions for SUD, relapse remains the norm. A recent meta analysis of 21 treatment outcome studies conducted between 2000–2015 found that fewer than 10% of treatment seekers were in remission in any given year following SUD treatment .