Despite positive signals from proof-of-concept studies and pilot RCTs, they require replication and testing with suitable control conditions in order to demonstrate their applicability in clinical settings. These limitations highlight the need for a harmonization approach that promotes greater standardization in cognitive training protocols and assessment of its effectiveness . Since the software and manuals of some of the most promising interventions are well-developed and reproducible, we should advance towards optimized shared protocols that can promote international collaborations and multi-site studies. These recommendations will elucidate what works, for whom and under what conditions . This knowledge will then guide the adoption of CT to improve outcomes for people seeking treatment for SUD.The exponential growth in our understanding of the neural circuits involved in drug addiction over the last 20 years has been accompanied by the introduction of non-invasive brain stimulation technologies capable of modulating brain circuits externally , such as transcranial magnetic stimulation and transcranial electrical stimulation . Technical advances in NIBS has increased hopes to find clinical applications for NIBS in addiction medicine . New FDA approval of NIBS technologies in depressive and obsessive-compulsive disorders, which have overlapping brain circuits with SUD, has raised these expectations to a higher level. There are other emerging areas of NIBS for addiction medicine, such as focused ultrasound stimulation and transcranial nerve stimulation . Furthermore, other technologies exist that target neural circuits non-invasively that can be classified as “neuromodulation”,indoor hydroponic system such as fMRI- or EEG-neuro feedback , whereby individuals can change their own brain activity in real time using a brain-computer interface. However, this section will primarily focus on tES/TMS/NF.
We will review potential targets, ideal scenarios, and complexities in the field of neuromodulation for addiction treatment and then conclude with a few recommendations for future research.Targets in the field of neuromodulation should be defined across multiple levels, from behavior, cognitive process, and neural circuit. The NIMH research domain criteria have provided a research framework for mental health disorders that include these levels of targets for neuroscience-informed interventions including neuromodulation. While this framework was not specifically designed for addiction science, it is still a helpful resource. In RDoC terminologies, three main domains are more frequently considered for addiction medicine: positive valence, negative valence, and cognitive systems with a predominant focus on EF . Within the positive valence domain, non-drug and drug-related reward processing are the most favorable multi-level targets for addiction treatment. Within the negative valence domain, acute or chronic withdrawal/negative reinforcement, anhedonia, and negative mood/anxiety comorbidities should be considered. EF with a broad definition has also potential to be targeted in neuromodulation . For more details, please see Table 1.There is a trend of reporting positive results in tDCS and rTMS trials in SUD that is being reflected in systematic reviews and meta-analysis. In a meta-analysis published in 2013 on 17 eligible trials, Jansen, et al., reported that rTMS and tDCS on DLPFC could decrease drug craving . A meta-analysis of 10 rTMS studies identified a beneficial effect of high-frequency rTMS on craving associated with nicotine use disorder but not alcohol . Another meta-analysis published in 2018 by Song, et al., including 48 tDCS and rTMS studies targeting the DLPFC, reported positive overall effects on reducing drug craving and consumption with larger effect for multi-session interventions compared to single session interventions . A recent meta-analysis with 15 studies using tDCS among nicotine dependents reported positive effect on craving and consumption . However, there is a large variation in methodological details that makes it hard to find trials replicating previous findings using same stimulation protocols.
Some of these methodological variations are being introduced below with few examples. Figure 1 depicts the distribution of published tES/TMS studies based on their target areas. Most but not all published tES/TMS studies have targeted the DLPFC in order to indirectly target other areas within the EF network or other limbic/paralimbic areas through their connections to the DLPFC. As an example, Terraneo et al. showed that applying 15-Hz stimulation to the left DLPFC can reduce self-reported craving [visual analogue scale ] and cocaine use among patients with cocaine use disorder randomized to receive active or sham repetitive TMS. In another study, Yang et al. showed that electrical stimulation over the DLPFC helps lower cigarette craving in nicotine-dependent individuals . Participant smokers underwent 1 session of real and sham transcranial direct current stimulation in a cross-over setting with 30 min duration and 1-mA intensity. There are studies targeting other areas than the DLPFC within the frontal cortex, such as inferior frontal gyrus, ventromedial prefrontal, or middle frontal cortices. As an example, Kearney-Ramos et al. demonstrated that applying continuous theta burst stimulationas a type of TMS to the ventromedial prefrontal cortex could attenuate the cue related functional connectivity . In another study, Ceccanti et al. found out that deep TMS on the medial prefrontal cortex decreased craving and alcohol intake in people with alcohol use disorder. There are also studies targeting motor cortex and temporoparietal areas which have shown that tDCS reduces behavior in tobacco users. To conclude , the distribution of international resources across all these circuit/process/behavior targets provides interesting explorative results to date. Ignoring these methodological variations could result in positive results in meta-analysis reports. However, considering these methodological details would make it hard to introduce a stimulation protocol with enough evidence for clinical use. There is a critical need in the international NIBS research community to focus on one or two main targets to explore any potentially replicable effects that could determine suitable avenues for clinical application.
Application of other areas of NIBS such as FUS, tNS in addiction medicine is limited to a few case reports. Beyond NIBS, invasive brain stimulation technologies like deep brain stimulation are only just emerging as approaches in addiction medicine with only a few case reports or pilot trials in the literature. Consequently, the lack of robust evidence for invasive neuromodulation precludes any judgment regarding its clinical utility.There are 96 original tES/TMS publications in addiction medicine as of May 1, 2019 mainly reporting positive results with one to over 20 sessions of stimulation . Large space of methodological parameters to select from, small sample sizes, and lack of replication across different labs make it difficult to draw firm conclusions regarding its effectiveness. Published tES/TMS evidence for addiction treatment has been generated by labs in 14 countries so far . To focus these efforts, there is a need for an international road map to harmonize the current activities in the field across the world using methodologically rigorous designs. We hope ISAM-NIG along with other international collaborative networks like International Network of tES/TMST rials for Addiction Medicine can serve to develop and navigate this road map. The ISAM-NIG neuromodulation road map should also align with ISAM-NIG road maps in other areas like brain imaging, cognitive assessments or cognitive training, and this publication is the first attempt at this initiative. These domains of clinical addiction neuroscience can then work hand-in-hand to create tangible outcomes in daily clinical practice. Real-time neuro feedback allows online voluntary regulation of brain activity and has shown promise to enhance ascribed cognitive processes in health and psychopathology . Participants can monitor their brain function in real time through a brain computer interface ,microgreen flood table typically showing a thermometer representing the “temperature” of which increases/decreases in real time, to reflect changes in the level of brain function. Neuro feedback aids participants to voluntarily change brain function online using distinct cognitive strategies . Neuro feedback has been most consistently tested in ADHD and other psychopathologies, with very early evidence being available in SUD.As core brain dysfunction is identified within a SUD, neuro feedback can be used as a personalized intervention to enhance and recover underlying dysfunctional neurocognitive pathways. Neuro feedback can source and target brain activity using distinct brain imaging techniques including EEG and fMRI . EEG-based neuro feedback allows individuals to modulate the intensity of brain oscillations at specific frequencies . These protocols have often been used in conjunction with sensorimotor rhythm training to improve efficacy in SUD. EEG-based neuro feedback studies have targeted brain function in varying SUD groups including alcohol, opioid, and stimulant use disorders [see detailed review here ]. This body of work led to mixed evidence of effects on abstinence in the week and months following neuro feedback training, as well as reduced disinhibition, craving, and severity of dependence symptoms. A paucity of studies has shown that these effects were stronger when EEG neuro feedback was used in conjunction with existing standard psychological, pharmacological, and rehabilitation treatments.
Real-time fMRI -based neuro feedback has the potential to provide insight in understanding the mechanisms of SUD underpinned by deep brain nuclei [e.g., striatum, amygdala ] the activity of which is unlikely to be robustly measured via surface EEG. Feedback can be provided on the level of activity of single or multiple a priori regions of interest, the strength of the connectivity between multiple regions, and patterns of brain activity identified with machine learning methods. A handful of studies have used rtfMRI neuro feedback in SUD [for a review, see ]. This body of work focused largely on nicotine and alcohol use disorders . Most of these studies focused on a priori brain regions of interest, most commonly the anterior cingulate cortex, medial prefrontal cortex, and other regions—as well as brain connectivity—were used as source for feedback from single studies . Several neuro feedback studies required participants to modulate brain function during craving tasks . This body of work shows that patients could modulate brain function in the target regions, and provides mixed evidence on the presence and absence of associations between changes in brain activity/connectivity and the severity of drug craving. In EEG and rtfMRI neuro feedback studies, the significant lack of active placebo controlled and well-powered studies warrants the conduct of more systematic work to determine the efficacy of rEEG and rtfMRI-based neuro feedback.Alcohol use is exceedingly common during adolescence, with rates of past year alcohol use in the US increasing from 24% to 64%, and past year drunkenness rising from 9% to 45% from ages 12 to 18 . Furthermore, almost a quarter of US 18 year olds report heavy episodic drinking, defined as consuming five or more drinks on one occasion, during the past two weeks . These high rates of heavy alcohol use are concerning, as the adolescent brain undergoes extensive morphometric and functional maturation, including decreases in gray matter and increases in white matter volume . Gray matter reductions begin during early adolescenceand are generally considered to be related to pruning of excess neurons, changes in the extracellular matrix, and white matter encroachment , beginning primarily in posterior brain regions and progressing to more anterior regions with decreases in dorsal prefrontal cortical volume continuing into early adulthood. In tandem with cortical thinning, white matter volumes increases over adolescence, due to myelination of white matter tracts . These co-occurring processes are an integral component of neurocognitive development, creating more localized and efficient information processing and improved cognition . Because of these extensive maturational changes, the developing adolescent brain may be more vulnerable to the deleterious effects of alcohol . Heavy alcohol use during adolescence has been cross-sectionally associated with disadvantages on several neuropsychological domains, including memory, executive functioning, visuospatial skills, and sustained attention . Importantly, longitudinal studies have suggested an adverse influence of adolescent heavy drinking on the development of visuospatial processing, attention, and working memory . Furthermore, deficits on tasks of inhibitory functioning in substance-naïve youth have been related to initiation of heavy alcohol use by ages 17–18 , suggesting cognitive functioning is both predictive of, and affected by, alcohol use. The underlying mechanism of these behavioral changes may be related to morphometric anomalies in brain volume or cortical thickness. Research using structural magnetic resonance imaging has shown smaller hippo campal , prefrontal cortex , and cerebellum volumes in heavy-drinking teens compared to non-using controls. In a recent longitudinal study in youth characterized before and after initiating heavy alcohol use, adolescents who began heavy drinking over the follow-up period showed accelerated cortical thinning of right middle frontal gyrus, as well as decreased white matter volume, when compared to demographically matched non-using teens .