Outcome of Non-Invasive Brain Stimulation in Substance Use Disorders: A Review of Randomized Sham-Controlled Clinical Trials.

Non-invasive brain stimulation (NIBS) might be a new approach to treat substance use disorders (SUD). A systematic review and critical analysis was performed to identify potential therapeutic effects of NIBS on addictions. A search of the Medline database was conducted for randomized sham-controlled trials using NIBS in the field of addiction and published until August 2016. Twenty-six studies in various SUD met the inclusion criteria. Converging evidence indicates that NIBS might be a promising mean to treat patients with alcohol and tobacco use disorders, by acting on craving reduction and other mechanisms such as improvement in cognitive dysfunctions.

The morphological and molecular changes of brain cells exposed to direct current electric field stimulation.

BACKGROUND: The application of low-intensity direct current electric fields has been experimentally used in the clinic to treat a number of brain disorders, predominantly using transcranial direct current stimulation approaches. However, the cellular and molecular changes induced by such treatment remain largely unknown. METHODS: Here, we tested various intensities of direct current electric fields (0, 25, 50, and 100V/m) in a well-controlled in vitro environment in order to investigate the responses of neurons, microglia, and astrocytes to this type of stimulation. This included morphological assessments of the cells, viability, as well as shape and fiber outgrowth relative to the orientation of the direct current electric field. We also undertook enzyme-linked immunosorbent assays and western immunoblotting to identify which molecular pathways were affected by direct current electric fields. RESULTS: In response to direct current electric field, neurons developed an elongated cell body shape with neurite outgrowth that was associated with a significant increase in growth associated protein-43. Fetal midbrain dopaminergic explants grown in a collagen gel matrix also showed a reorientation of their neurites towards the cathode. BV2 microglial cells adopted distinct morphological changes with an increase in cyclooxygenase-2 expression, but these were dependent on whether they had already been activated with lipopolysaccharide. Finally, astrocytes displayed elongated cell bodies with cellular filopodia that were oriented perpendicularly to the direct current electric field. CONCLUSION: We show that cells of the central nervous system can respond to direct current electric fields both in terms of their morphological shape and molecular expression of certain proteins, and this in turn can help us to begin understand the mechanisms underlying the clinical benefits of direct current electric field.

Influencing Human Behavior with Noninvasive Brain Stimulation: Direct Human Brain Manipulation Revisited.

The use of tools to perturb brain activity can generate important insights into brain physiology and offer valuable therapeutic approaches for brain disorders. Furthermore, the potential of such tools to enhance normal behavior has become increasingly recognized, and this has led to the development of various noninvasive technologies that provides a broader access to the human brain. While providing a brief survey of brain manipulation procedures used in the past decades, this review aims at stimulating an informed discussion on the use of these new technologies to investigate the human. It highlights the importance to revisit the past use of this unique armamentarium and proceed to a detailed analysis of its present state, especially in regard to human behavioral regulation.

Changes in resting-state functional MRI connectivity during and after transcranial direct current stimulation in healthy adults.

Introduction: Transcranial direct current stimulation (tDCS) applied over the dorsolateral prefrontal cortex (DLPFC) at rest can influence behaviors. However, its mechanisms remain poorly understood. This study examined the effect of a single session of tDCS over the bilateral DLPFC on resting-state functional connectivity using fMRI (rs-fcMRI) during and after stimulation in healthy adults. We also investigated whether baseline rs-fcMRI predicted tDCS-induced changes in rs-fcMRI. Methods: This was a randomized, sham-controlled, double-blind, crossover study. We delivered tDCS for 30 min at 1 mA with the anode and cathode over the left and right DLPFC, respectively. We used seed-based analyses to measure tDCS-induced effects on whole-brain rs-fcMRI using a 3 (before, during, after stimulation) × 2 (active, sham stimulation) ANOVA. Results: There were four significant Time × Stimulation interactions on the connectivity scores with the left DLPFC seed (under the anode electrode) and no interactions for the right DLPFC seed (under the cathode electrode). tDCS changed rs-fcMRI between the left DLPFC seed and parieto-occipital, parietal, parieto-occipitotemporal, and frontal clusters during and after stimulation, as compared to sham. Furthermore, rs-fcMRI prior to stimulation predicted some of these tDCS-induced changes in rs-fcMRI during and after stimulation. For instance, rs-fcMRI of the fronto-parietooccipital network predicted changes observed after active stimulation, rs-fcMRI of the fronto-parietal network predicted changes during active stimulation, whereas rs-fcMRI of the fronto-parieto-occipitotemporal and the frontal networks predicted changes both during and after active stimulation. Discussion: Our findings reveal that tDCS modulated rs-fcMRI both during and after stimulation mainly in regions distal, but also in those proximal to the area under the anode electrode, which were predicted by rs-fcMRI prior to tDCS. It might be worth considering rs-fcMRI to optimize response to tDCS.

Abnormal modulation of corticospinal excitability in adults with Asperger's syndrome.

Most candidate genes and genetic abnormalities linked to autism spectrum disorders (ASD) are thought to play a role in developmental and experience-dependent plasticity. As a possible index of plasticity, we assessed the modulation of motor corticospinal excitability in individuals with Asperger's syndrome (AS) using transcranial magnetic stimulation (TMS). We measured the modulatory effects of theta-burst stimulation (TBS) on motor evoked potentials (MEPs) induced by single-pulse TMS in individuals with AS as compared with age-, gender- and IQ-matched neurotypical controls. The effect of TBS lasted significantly longer in the AS group. The duration of the TBS-induced modulation alone enabled the reliable classification of a second study cohort of subjects as AS or neurotypical. The alteration in the modulation of corticospinal excitability in AS is thought to reflect aberrant mechanisms of plasticity, and might provide a valuable future diagnostic biomarker for the disease and ultimately offer a target for novel therapeutic interventions.

Whole-brain morphometry in Canadian soldiers with posttraumatic stress disorder.

Patients with posttraumatic stress disorder (PTSD) display several structural brain differences when compared with healthy individuals. However, findings are particularly inconsistent for soldiers with PTSD. Here, we characterized the brain morphometry of 37 soldiers from the Canadian Armed Forces with adulthood war-related PTSD using structural magnetic resonance imaging. We assessed time since trauma, as well as PTSD, depressive, and anxiety symptoms with the Modified PTSD Symptoms Scale, Beck Depression Inventory, and Beck Anxiety Inventory, respectively. Whole-brain morphometry was extracted with FreeSurfer and compared with a validated normative database of more than 2700 healthy individuals. Volume and thickness from several regions differed from the norms. Frontal regions were smaller and thinner, particularly the superior and rostral middle frontal gyri. Furthermore, smaller left rostral middle frontal gyrus, left pericalcarine cortex, and right fusiform gyrus were associated with more recent trauma. All subcortical structures were bigger, except the hippocampus. These findings suggest a particular brain morphometric signature of PTSD in soldiers. Smaller and thinner frontal and larger subcortical regions support impaired top-down and/or downregulation of emotional response in PTSD. Finally, the correlation of smaller frontal, temporal, and occipital regions with more recent trauma might inform future therapeutic approaches.

Non-invasive brain stimulation and neuroenhancement.

Attempts to enhance human memory and learning ability have a long tradition in science. This topic has recently gained substantial attention because of the increasing percentage of older individuals worldwide and the predicted rise of age-associated cognitive decline in brain functions. Transcranial brain stimulation methods, such as transcranial magnetic (TMS) and transcranial electric (tES) stimulation, have been extensively used in an effort to improve cognitive functions in humans. Here we summarize the available data on low-intensity tES for this purpose, in comparison to repetitive TMS and some pharmacological agents, such as caffeine and nicotine. There is no single area in the brain stimulation field in which only positive outcomes have been reported. For self-directed tES devices, how to restrict variability with regard to efficacy is an essential aspect of device design and function. As with any technique, reproducible outcomes depend on the equipment and how well this is matched to the experience and skill of the operator. For self-administered non-invasive brain stimulation, this requires device designs that rigorously incorporate human operator factors. The wide parameter space of non-invasive brain stimulation, including dose (e.g., duration, intensity (current density), number of repetitions), inclusion/exclusion (e.g., subject's age), and homeostatic effects, administration of tasks before and during stimulation, and, most importantly, placebo or nocebo effects, have to be taken into account. The outcomes of stimulation are expected to depend on these parameters and should be strictly controlled. The consensus among experts is that low-intensity tES is safe as long as tested and accepted protocols (including, for example, dose, inclusion/exclusion) are followed and devices are used which follow established engineering risk-management procedures. Devices and protocols that allow stimulation outside these parameters cannot claim to be "safe" where they are applying stimulation beyond that examined in published studies that also investigated potential side effects. Brain stimulation devices marketed for consumer use are distinct from medical devices because they do not make medical claims and are therefore not necessarily subject to the same level of regulation as medical devices (i.e., by government agencies tasked with regulating medical devices). Manufacturers must follow ethical and best practices in marketing tES stimulators, including not misleading users by referencing effects from human trials using devices and protocols not similar to theirs.

Brain stimulation over Broca's area differentially modulates naming skills in neurotypical adults and individuals with Asperger's syndrome.

In the present study we tested the hypothesis that, in subjects with Asperger's syndrome (ASP), the dynamics of language-related regions might be abnormal, so that repetitive transcranial magnetic stimulation (rTMS) over Broca's area leads to differential behavioral effects as seen in neurotypical controls. We conducted a five-stimulation-site, double-blind, multiple crossover, pseudo-randomized, sham-controlled study in 10 individuals with ASP and 10 age- and gender-matched healthy subjects. Object naming was assessed before and after low-frequency rTMS of the left pars opercularis, left pars triangularis, right pars opercularis and right pars triangularis, and sham stimulation, as guided stereotaxically by each individual's brain magnetic resonance imaging. In ASP participants, naming improved after rTMS of the left pars triangularis as compared with sham stimulation, whereas rTMS of the adjacent left opercularis lengthened naming latency. In healthy subjects, stimulation of parts of Broca's area did not lead to significant changes in naming skills, consistent with published data. Overall, these findings support our hypothesis of abnormal language neural network dynamics in individuals with ASP. From a methodological point of view, this work illustrates the use of rTMS to study the dynamics of brain-behavior relations by revealing the differential behavioral impact of non-invasive brain stimulation in a neuropsychiatric disorder.

Impact of bifrontal transcranial Direct Current Stimulation on decision-making and stress reactivity. A pilot study.

Stress is an adaptive response with repercussions on the human health. The dorsolateral prefrontal cortex (DLPFC) is thought to be involved in stress regulation by contributing to limit its biological and behavioral pejorative consequences. Here, to investigate the contribution of the DLPFC in stress response, we applied transcranial Direct Current Stimulation (tDCS) over the DLPFC during acute stress exposure in healthy participants. We hypothesized that active tDCS compared to sham would impact top-down control of the DLPFC on goal-directed behavior and hypothalamo-pituitary-adrenal (HPA) axis activity. In a double-blind sham-controlled study, 30 healthy subjects were randomly allocated to receive either active (2 mA, n = 15) or sham tDCS (n = 15) with the anode over the left DLPFC and the cathode over the right DLFPC. During the 30-min stimulation period, participants faced an experimental acute stress paradigm. Changes in goal-directed behavior were measured with a decision-making task. HPA axis reactivity was assessed by repeated measures of salivary cortisol. Acute stress decreased appetite for immediate reward in the sham group (mean - 4.40%; p = 0.017) whereas no significant effect of stress was observed in the active group. During stress exposure, we observed a significant larger elevation of salivary cortisol (p = 0.045; Cohen's d = 0.431) in the sham tDCS group (+179.8%; Standard error of the mean (SEM) = 20.6) than in the active group (+138.5%; SEM = 14.2). Stimulating the DLPFC using bifrontal tDCS may prevent stress-induced acute effects on both biological and behavioral outcomes.

Non-invasive neuromodulation for tinnitus: A meta-analysis and modeling studies.

BACKGROUND: Patients with tinnitus often have poor quality of life, as well as severe anxiety and depression. New approaches to treat tinnitus are needed. OBJECTIVE: Evaluate the effects of non-invasive neuromodulation on tinnitus through a metaanalysis and modeling study. The main hypothesis was that real as compared to sham neuromodulation that decreases tinnitus will modulate regions in line with the neurobiological models of tinnitus. METHODS AND RESULTS: The systematic review, conducted from Pubmed, Cochrane and PsycINFO databases, showed that active as compared to sham repetitive transcranial magnetic stimulation (rTMS) reduced tinnitus, but active and sham transcranial direct current stimulation did not significantly differ. Further, rTMS over the auditory cortex was the most effective protocol. The modeling results indicate that this rTMS protocol elicited the strongest electric fields in the insula. Also, rTMS was particularly beneficial in women. Finally, the placebo effects were highly variable, highlighting the importance of conducting sham-controlled trials. CONCLUSION: In sum, neuromodulation protocols that target the auditory cortex and the insula may hold clinical potential to treat tinnitus.

Neurostimulation for Stroke Rehabilitation.

Neurological injuries such as strokes can lead to important loss in motor function. Thanks to neuronal plasticity, some of the lost functionality may be recovered over time. However, the recovery process is often slow and incomplete, despite the most effective conventional rehabilitation therapies. As we improve our understanding of the rules governing activity-dependent plasticity, neuromodulation interventions are being developed to harness neural plasticity to achieve faster and more complete recovery. Here, we review the principles underlying stimulation-driven plasticity as well as the most commonly used stimulation techniques and approaches. We argue that increased spatiotemporal precision is an important factor to improve the efficacy of neurostimulation and drive a more useful neuronal reorganization. Consequently, closed-loop systems and optogenetic stimulation hold theoretical promise as interventions to promote brain repair after stroke.

Brain morphometry in adults with gambling disorder.

Little is known regarding the brain substrates of Gambling Disorder, including surface brain morphometry, and whether these are linked to the clinical profile. A better understanding of the brain substrates will likely help determine targets to treat patients. Hence, the aim of this study was two-fold, that is to examine surface-based morphometry in 17 patients with gambling disorder as compared to norms of healthy individuals (2713 and 2790 subjects for cortical and subcortical anatomical scans, respectively) and to assess the clinical relevance of morphometry in patients with Gambling Disorder. This study measured brain volume, surface and thickness in Gambling Disorder. We compared these measures to those of a normative database that controlled for factors such as age and sex. We also tested for correlations with gambling-related behaviors, such as gambling severity and duration, impulsivity, and depressive symptoms (assessed using the South Oaks Gambling Screen, years of gambling, Barratt Impulsiveness Scale, and Beck Depression Inventory, respectively). Patients displayed thinner prefrontal and parietal cortices, greater volume and thickness of the occipital and the entorhinal cortices, and greater volume of subcortical regions as compared to the norms of healthy individuals. There were positive correlations between surface area of occipital regions and depressive symptoms. This work contributes to better characterize the brain substrates of Gambling Disorder, which appear to resemble those of substance use disorders and Internet Gaming Disorder.

Concurrent Transcranial Direct Current Stimulation and Resting-State Functional Magnetic Resonance Imaging in Patients with Gambling Disorder.

Background/Introduction: Transcranial direct current stimulation (tDCS) delivered over the dorsolateral prefrontal cortex (DLPFC) while patients are at rest can decrease craving in patients with substance-related and addictive disorders. Yet, the effects of tDCS on resting-state brain activity remain unknown in this population. This study examined the effects of tDCS on resting-state functional connectivity (rsFC) with concurrent stimulation and functional magnetic resonance imaging in patients with gambling disorder. Methods: This was a randomized, sham-controlled, double-blind, crossover study. The anodal and cathodal electrodes were applied over the right and left DLPFC, respectively. Patients received 30 min of active and sham stimulation on separate days. rsFC was assessed before and during stimulation with seed-based analyses. Results: There was a significant increase of rsFC between the right DLPFC seed and the right superior parietal lobule during active stimulation as compared to during sham stimulation (p = 0.0059, corrected for multiple comparisons). There was also a positive correlation between rsFC change of this frontoparietal network and brain volume of the right DLPFC (p = 0.0042, corrected for multiple comparisons). Discussion: A single session of tDCS targeting the DLPFC strengthened functional connectivity in a frontoparietal circuit, known to be implicated in cognitive control, especially in patients with a greater volume of the region under the anode electrode. Impact statement Transcranial direct current stimulation increased the functional connectivity of a frontoparietal circuit in patients with gambling disorder. These changes were larger in patients with greater volume of the dorsolateral prefrontal cortex. Transcranial direct current stimulation strengthened the connectivity of a brain network known to be associated with cognitive control.

Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee.

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines.

Modulation of cortical motor outputs by the symbolic meaning of visual stimuli.

The observation of an action modulates motor cortical outputs in specific ways, in part through mediation of the mirror neuron system. Sometimes we infer a meaning to an observed action based on integration of the actual percept with memories. Here, we conducted a series of experiments in healthy adults to investigate whether such inferred meanings can also modulate motor cortical outputs in specific ways. We show that brief observation of a neutral stimulus mimicking a hand does not significantly modulate motor cortical excitability (Study 1) although, after prolonged exposure, it can lead to a relatively nonspecific modulation (Study 2). However, when such a neutral stimulus is preceded by exposure to a hand stimulus, the latter appears to serve as a prime, perhaps enabling meaning to the neutral stimulus, which then modulates motor cortical excitability in accordance with mirror neuron-driving properties (Studies 2 and 3). Overall results suggest that a symbolic value ascribed to an otherwise neutral stimulus can modulate motor cortical outputs, revealing the influence of top-down inputs on the mirror neuron system. These findings indicate a novel aspect of the human mirror neuron system: an otherwise neutral stimulus can acquire specific mirror neuron-driving properties in the absence of a direct association between motor practice and perception. This significant malleability in the way that the mirror neuron system can code otherwise meaningless (i.e. arbitrarily associated) stimuli may contribute to coding communicative signals such as language. This may represent a mirror neuron system feature that is unique to humans.

Modulation of decision-making in a gambling task in older adults with transcranial direct current stimulation.

Cognitive performance usually declines in older adults as a result of neurodegenerative processes. One of the cognitive domains usually affected is decision-making. Based on our recent findings suggesting that non-invasive brain stimulation can improve decision-making in young participants, we studied whether bifrontal transcranial direct current stimulation (tDCS) applied over the right and left prefrontal cortex of older adult subjects can change balance of risky and safe responses as it can in younger individuals. Twenty-eight subjects (age range from 50 to 85 years) performed a gambling risk task while receiving either anodal tDCS over the right and cathodal tDCS over the left dorsolateral prefrontal cortex (DLPFC), anodal tDCS over the left with cathodal tDCS over the right DLPFC, or sham stimulation. Our main finding was a significant group effect showing that participants receiving left anodal/right cathodal stimulation chose more often high-risk prospects as compared with participants receiving sham or those receiving right anodal/left cathodal stimulation. This result is contrary to previous findings in young subjects, suggesting that modulation of cortical activity in young and elderly results in opposite behavioral effects; thus supporting fundamental changes in cognitive processing in the elderly.

Neuromodulation of decision-making in the addictive brain.

Noninvasive brain stimulation of the dorsolateral prefrontal cortex with repetitive transcranial magnetic stimulation and transcranial direct current stimulation can modify decision-making behaviors in healthy subjects. The same type of noninvasive brain stimulation can suppress drug craving in substance user patients, who often display impaired decision-making behaviors. We discuss the implications of these studies for the cognitive neurosciences and their translational applications to the treatment of addictions. We propose a neurocognitive model that can account for our findings and suggests a promising therapeutic role of brain stimulation in the treatment of substance abuse and addictive behavior disorders.

Patterns of Intrahemispheric EEG Asymmetry in Insomnia Sufferers: An Exploratory Study.

Individuals with insomnia present unique patterns of electroencephalographic (EEG) asymmetry between homologous regions of each brain hemisphere, yet few studies have assessed asymmetry within the same hemisphere. Increase in intrahemispheric asymmetry during rapid eye movement (REM) sleep in good sleepers (GS) and disruption of REM sleep in insomnia sufferers (INS) both point out that this activity may be involved in the pathology of insomnia. The objective of the present exploratory study was to evaluate and quantify patterns of fronto-central, fronto-parietal, fronto-occipital, centro-parietal, centro-occipital and parieto-occipital intrahemispheric asymmetry in GS and INS, and to assess their association with sleep-wake misperception, daytime anxiety and depressive symptoms, as well as insomnia severity. This paper provides secondary analysis of standard EEG recorded in 43 INS and 19 GS for three nights in a sleep laboratory. Asymmetry measures were based on EEG power spectral analysis within 0.3-60 Hz computed between pairs of regions at frontal, central, parietal and occipital derivations. Repeated-measures ANOVAs were performed to assess group differences. Exploratory correlations were then performed on asymmetry and sleep-wake misperception, as well as self-reported daytime anxiety and depressive symptoms, and insomnia severity. INS presented increased delta and theta F3/P3 asymmetry during REM sleep compared with GS, positively associated with depressive and insomnia complaints. INS also exhibited decreased centro-occipital (C3/O1, C4/O2) and parieto-occipital (P3-O1, P4/O2) theta asymmetry during REM. These findings suggest that INS present specific patterns of intrahemispheric asymmetry, partially related to their clinical symptoms. Future studies may investigate the extent to which asymmetry is related to sleep-wake misperception or memory impairments.

Eye tracking of smoking-related stimuli in tobacco use disorder: A proof-of-concept study combining attention bias modification with alpha-transcranial alternating current stimulation.

BACKGROUND: Tobacco use disorder (TUD) is characterized by the presence of an attentional bias (AB) towards smoking-related stimuli. We investigated whether combining an AB modification paradigm (ABM) with transcranial alternating current stimulation (tACS) applied over the dorsolateral prefrontal cortex (DLPFC) reduces the AB towards smoking-related stimuli, as well as craving level and impulsive choices. METHODS: In a sham-controlled, crossover preliminary study, 19 subjects with TUD received two stimulation arms: 1) active tACS (10 Hz, 2 mA, 30 min) combined with ABM and 2) sham tACS combined with ABM, in a randomized order, separated by one week. AB towards smoking cues during passive observation of smoking and neutral cues was assessed with an eye-tracking device and reactions times at a visual-probe task. Craving level was measured with the Questionnaire of Smoking Urges. Impulsive choices were assessed with the delay discounting task. RESULTS: Active tACS combined with ABM reduced the amount of time spent looking at smoking-related pictures (p = 0.03), prevented the increase of self-reported desire to smoke (p = 0.026), and reduced the proportion of impulsive choices (p = 0.049), compared to sham tACS combined with ABM. No significant effects were reported on other craving dimensions and on AB based on reaction times. CONCLUSIONS: These preliminary findings suggest that combining tACS with ABM may help smokers who wish to quit by reducing the desire to smoke, attention to smoking-cues, and impulsive decision-making.

Semantic Processing in Healthy Aging and Alzheimer's Disease: A Systematic Review of the N400 Differences.

Semantic deficits are common in individuals with Alzheimer's disease (AD). These deficits notably impact the ability to understand words. In healthy aging, semantic knowledge increases but semantic processing (i.e., the ability to use this knowledge) may be impaired. This systematic review aimed to investigate semantic processing in healthy aging and AD through behavioral responses and the N400 brain event-related potential. The results of the quantitative and qualitative analyses suggested an overall decrease in accuracy and increase in response times in healthy elderly as compared to young adults, as well as in individuals with AD as compared to age-matched controls. The influence of semantic association, as measured by N400 effect amplitudes, appears smaller in healthy aging and even more so in AD patients. Thus, semantic processing differences may occur in both healthy and pathological aging. The establishment of norms of healthy aging for these outcomes that vary between normal and pathological aging could eventually help early detection of AD.