A pilot, randomized clinical trial: Left dorsolateral prefrontal cortex intermittent theta burst stimulation improves treatment outcomes in veterans with alcohol use disorder.

BACKGROUND: Transcranial magnetic stimulation (TMS) offers a promising treatment avenue to modulate brain function in alcohol use disorder (AUD). To the best of our knowledge, this pilot study is the first randomized, double-blind, sham-controlled trial to deliver intermittent theta burst stimulation to the left dorsolateral prefrontal cortex (DLPFC) among US veterans with AUD. We hypothesized that 20 sessions of real TMS are tolerable and feasible. As a secondary line of inquiry, we hypothesized that, relative to sham TMS, individuals receiving real TMS would experience greater reductions in 6-month relapse rates, anhedonia, and alcohol cue-reactivity. METHODS: Veterans (n = 17, one woman) were enrolled in a double-blind, sham-controlled trial (2-3 sessions/day; 7-10 days; 600 pulses/session; 20 sessions). Pre- and posttreatment assessments included responses to self-report questionnaires and functional magnetic resonance imaging measures of alcohol cue-reactivity. Alcohol consumption was assessed for 6 months. Linear mixed-effects models were constructed to predict posttreatment craving, mood, and cue-reactivity. RESULTS: Individuals who received active iTBS (n = 8) were less likely to relapse within 3 months after treatment than the sham-treated group (n = 9) (OR = 12.0). Greater reductions in anhedonia were observed following active iTBS (Cohen's d = -0.59), relative to sham (d = -0.25). Alcohol cue-reactivity was reduced following active iTBS and increased following sham within the left insula (d = -0.19 vs. 0.51), left thalamus (d = -0.28 vs. 0.77), right insula (d = 0.18 vs. 0.52), and right thalamus (d = -0.06 vs. 0.62). CONCLUSIONS: Relative to sham, we demonstrate that 20 sessions of real left DLPFC iTBS reduced the likelihood of relapse for at least 3 months. The potential utility of this approach is underscored by observed decreases in anhedonia and alcohol cue-reactivity-strong predictors of relapse among veterans. These initial data offer a valuable set of effect sizes to inform future clinical trials in this patient population.

Blunted Neurobehavioral Loss Anticipation Predicts Relapse to Stimulant Drug Use.

BACKGROUND: Patients with stimulant use disorder experience high rates of relapse. While neurobehavioral mechanisms involved in initiating drug use have been studied extensively, less research has focused on relapse. METHODS: To assess motivational processes involved in relapse and diagnosis, we acquired functional magnetic resonance imaging responses to nondrug (monetary) gains and losses in detoxified patients with stimulant use disorder (n = 68) and community control participants (n = 42). In a prospective multimodal design, we combined imaging of brain function, brain structure, and behavior to longitudinally track subsequent risk for relapse. RESULTS: At the 6-month follow-up assessment, 27 patients remained abstinent, but 33 had relapsed. Patients with blunted anterior insula (AIns) activity during loss anticipation were more likely to relapse, an association that remained robust after controlling for potential confounds (i.e., craving, negative mood, years of use, age, and gender). Lower AIns activity during loss anticipation was associated with lower self-reported negative arousal to loss cues and slower behavioral responses to avoid losses, which also independently predicted relapse. Furthermore, AIns activity during loss anticipation was associated with the structural coherence of a tract connecting the AIns and the nucleus accumbens, as was functional connectivity between the AIns and nucleus accumbens during loss processing. However, these neurobehavioral responses did not differ between patients and control participants. CONCLUSIONS: Taken together, the results of the current study show that neurobehavioral markers predicted relapse above and beyond conventional self-report measures, with a cross-validated accuracy of 72.7%. These findings offer convergent multimodal evidence that implicates blunted avoidance motivation in relapse to stimulant use and may therefore guide interventions targeting individuals who are most vulnerable to relapse.

Cultural variation in neural responses to social but not monetary reward outcomes.

European Americans view high-intensity, open-mouthed 'excited' smiles more positively than Chinese because they value excitement and other high arousal positive states more. This difference is supported by reward-related neural activity, with European Americans showing greater Nucleus Accumbens (NAcc) activity to excited (vs calm) smiles than Chinese. But do these cultural differences generalize to all rewards, and are they related to real-world social behavior? European American (N = 26) and Chinese (N = 27) participants completed social and monetary incentive delay tasks that distinguished between the anticipation and receipt (outcome) of social and monetary rewards while undergoing Functional Magnetic Resonance Imaging (FMRI). The groups did not differ in NAcc activity when anticipating social or monetary rewards. However, as predicted, European Americans showed greater NAcc activity than Chinese when viewing excited smiles during outcome (the receipt of social reward). No cultural differences emerged when participants received monetary outcomes. Individuals who showed increased NAcc activity to excited smiles during outcome had friends with more intense smiles on social media. These findings suggest that culture plays a specific role in modulating reward-related neural responses to excited smiles during outcome, which are associated with real-world relationships.

Ketamine's acute effects on negative brain states are mediated through distinct altered states of consciousness in humans.

Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain's affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals.

Disentangling the Skeins of Brain.

Some have argued that the brain is so complex that it cannot be understood using current reductive approaches. Drawing on examples from decision neuroscience, we instead contend that combining new neuroscientific techniques with reductive approaches that consider central brain components in time and space has generated significant progress over the past 2 decades. This progress has allowed researchers to advance from the scientific goals of description and explanation to prediction and control. Resulting knowledge promises to improve human health and well-being. As an alternative to the extremes of reductive versus emergent approaches, however, we propose a middle way of "expansion." This expansionist approach promises to leverage the specific spatial localization, temporal precision, and directed connectivity of central neural components to ultimately link levels of analysis.

Neural responses clarify how ecolabels promote sustainable purchases.

While behavioral and policy interventions such as ecolabels (e.g., the Energy Star label) promote sustainable purchases, the reason for their influence remains unclear. We combined incentive-compatible purchasing experiments, neuroimaging assessments, and a national stated choice survey to examine how the Energy Star label might influence choices of light bulbs within individuals, across individuals (n = 36), and out-of-sample in a national survey (n = 1550). Presence of the Energy Star label increased activity in neural regions associated with positive affective responses that predicted purchasing (e.g., the Nucleus Accumbens or NAcc), particularly in more impulsive individuals. Group-averaged NAcc activity could also account for consumer demand for similar sustainable product combinations in a national survey. These findings suggest that ecolabels may leverage affective responses in individuals as well as markets to promote sustainable purchases, which might inform the promotion of sustainable products.

Taking gambles at face value: Effects of emotional expressions on risky decisions.

Emotional facial expressions are ubiquitous and potent social stimuli that can signal favorable and unfavorable conditions. Previous research demonstrates that emotional expressions influence preference judgments, basic approach-avoidance behaviors, and reward learning. We examined whether emotional expressions can influence decisions such as choices between gambles. Based on theories of affective cue processing, we predicted greater risk taking after positive than negative expressions. This hypothesis was tested in four experiments across tasks that varied in implementation of risks, payoffs, probabilities, and temporal decision requirements. Facial expressions were presented unobtrusively and were uninformative about the choice. In all experiments, the likelihood of a risky choice was greater after exposure to positive versus neutral or negative expressions. Similar effects on risky choice occurred after presentation of different negative expressions (e.g., anger, fear, sadness, and disgust), suggesting involvement of general positive and negative affect systems. These results suggest that incidental emotional cues exert a valence-specific influence of on decisions, which could shape risk-taking behavior in social situations.

Longitudinal tracking of human plasma oxytocin suggests complex responses to moral elevation.

Positive social experiences may induce oxytocin release. However, previous studies of moral elevation have generally utilized cross-sectional and simple modeling approaches to establish the relationship between oxytocin and emotional stimuli. Utilizing a cohort of 30 non-lactating women (aged 23.6 ± 5.7 years), we tested whether exposure to a video identified as capable of eliciting moral elevation could change plasma oxytocin levels. Uniquely, we utilized a high-frequency longitudinal sampling approach and multilevel growth curve modeling with landmark registration to test physiological responses. The moral elevation stimulus, versus a control video, elicited significantly greater reports of being "touched/inspired" and "happy/joyful". However, the measured plasma oxytocin response was found to be markedly heterogeneous. While the moral elevation stimulus elicited increased plasma oxytocin as expected, this increase was only modestly larger than that seen following the control video. This increase was also only present in some individuals. We found no relationship between plasma oxytocin and self-report responses to the stimulus. From these data, we argue that future studies of the relationship between oxytocin and emotion need to anticipate heterogeneous responses and thus incorporate comprehensive individual psychological data; these should include evidence-based variables known to be associated with oxytocin such as a history of trauma, and the individual's psychological and emotional state at the time of testing. Given the complexity of physiological oxytocin release, such studies also need to incorporate frequent biological sampling to properly examine the dynamics of hormonal release and response.

Targeting the Salience Network: A Mini-Review on a Novel Neuromodulation Approach for Treating Alcohol Use Disorder.

Alcohol use disorder (AUD) continues to be challenging to treat despite the best available interventions, with two-thirds of individuals going on to relapse by 1 year after treatment. Recent advances in the brain-based conceptual framework of addiction have allowed the field to pivot into a neuromodulation approach to intervention for these devastative disorders. Small trials of repetitive transcranial magnetic stimulation (rTMS) have used protocols developed for other psychiatric conditions and applied them to those with addiction with modest efficacy. Recent evidence suggests that a TMS approach focused on modulating the salience network (SN), a circuit at the crossroads of large-scale networks associated with AUD, may be a fruitful therapeutic strategy. The anterior insula or dorsal anterior cingulate cortex may be particularly effective stimulation sites given emerging evidence of their roles in processes associated with relapse.

Brain tract structure predicts relapse to stimulant drug use.

Diffusion tractography allows identification and measurement of structural tracts in the human brain previously associated with motivated behavior in animal models. Recent findings indicate that the structural properties of a tract connecting the midbrain to nucleus accumbens (NAcc) are associated with a diagnosis of stimulant use disorder (SUD), but not relapse. In this preregistered study, we used diffusion tractography in a sample of patients treated for SUD (n = 60) to determine whether qualities of tracts projecting from medial prefrontal, anterior insular, and amygdalar cortices to NAcc might instead foreshadow relapse. As predicted, reduced diffusion metrics of a tract projecting from the right anterior insula to the NAcc were associated with subsequent relapse to stimulant use, but not with previous diagnosis. These findings highlight a structural target for predicting relapse to stimulant use and further suggest that distinct connections to the NAcc may confer risk for relapse versus diagnosis.

Replication of neural responses to monetary incentives and exploration of reward-influenced network connectivity in fibromyalgia.

Neuroimaging research has begun to implicate alterations of brain reward systems in chronic pain. Previously, using functional magnetic resonance imaging (fMRI) and a monetary incentive delay (MID) task, Martucci et al. (2018) showed that neural responses to reward anticipation and outcome are altered in fibromyalgia. In the present study, we aimed to test the replicability of these altered neural responses to reward in a separate fibromyalgia cohort. In addition, the present study was conducted at a distinct U.S. location but involved a similar study design. For the present study, 20 patients with fibromyalgia and 20 healthy controls participated in MID task fMRI scan procedures and completed clinical/psychological questionnaires. fMRI analyses comparing patient and control groups revealed a consistent trend of main results which were largely similar to the prior reported results. Specifically, in the replication fibromyalgia cohort, medial prefrontal cortex (MPFC) response was reduced during gain anticipation and was increased during no-loss (non-punishment) outcome compared to controls. Also consistent with previous findings, the nucleus accumbens response to gain anticipation did not differ in patients vs. controls. Further, results from similarly-designed behavioral, correlational, and exploratory analyses were complementary to previous findings. Finally, a novel network-based functional connectivity analysis of the MID task fMRI data across patients vs. controls implied enhanced connectivity within the default mode network in participants with fibromyalgia. Together, based on replicating prior univariate results and new network-based functional connectivity analyses of MID task fMRI data, we provide further evidence of altered brain reward responses, particularly in the MPFC response to reward outcomes, in patients with fibromyalgia.

Multi-band FMRI compromises detection of mesolimbic reward responses.

Recent innovations in Functional Magnetic Resonance Imaging (FMRI) have sped data collection by enabling simultaneous scans of neural activity in multiple brain locations, but have these innovations come at a cost? In a meta-analysis and preregistered direct comparison of original data, we examined whether acquiring FMRI data with multi-band versus single-band scanning protocols might compromise detection of mesolimbic activity during reward processing. Meta-analytic results (n = 44 studies; cumulative n = 5005 subjects) indicated that relative to single-band scans, multi-band scans showed significantly decreased effect sizes for reward anticipation in the Nucleus Accumbens (NAcc) by more than half. Direct within-subject comparison of single-band versus multi-band scanning data (multi-band factors = 4 and 8; n = 12 subjects) acquired during repeated administration of the Monetary Incentive Delay task indicated that reductions in temporal signal-to-noise ratio could account for compromised detection of task-related responses in mesolimbic regions (i.e., the NAcc). Together, these findings imply that researchers should opt for single-band over multi-band scanning protocols when probing mesolimbic responses with FMRI. The findings also have implications for inferring mesolimbic activity during related tasks and rest, for summarizing historical results, and for using neuroimaging data to track individual differences in reward-related brain activity.

Social media users produce more affect that supports cultural values, but are more influenced by affect that violates cultural values.

Although social media plays an increasingly important role in communication around the world, social media research has primarily focused on Western users. Thus, little is known about how cultural values shape social media behavior. To examine how cultural affective values might influence social media use, we developed a new sentiment analysis tool that allowed us to compare the affective content of Twitter posts in the United States (55,867 tweets, 1,888 users) and Japan (63,863 tweets, 1,825 users). Consistent with their respective cultural affective values, U.S. users primarily produced positive (vs. negative) posts, whereas Japanese users primarily produced low (vs. high) arousal posts. Contrary to cultural affective values, however, U.S. users were more influenced by changes in others' high arousal negative (e.g., angry) posts, whereas Japanese were more influenced by changes in others' high arousal positive (e.g., excited) posts. These patterns held after controlling for differences in baseline exposure to affective content, and across different topics. Together, these results suggest that across cultures, while social media users primarily produce content that supports their affective values, they are more influenced by content that violates those values. These findings have implications for theories about which affective content spreads on social media, and for applications related to the optimal design and use of social media platforms around the world. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Striatal and septo-hypothalamic responses to anticipation and outcome of affiliative rewards.

Humans are intrinsically motivated to bond with others. The ability to experience affiliative emotions (such as affection/tenderness, sexual attraction, and admiration/awe) may incentivize and promote these affiliative bonds. Here, we interrogate the role of the critical reward circuitry, especially the Nucleus Accumbens (NAcc) and the septo-hypothalamic region, in the anticipation of and response to affiliative rewards using a novel incentive delay task. During Functional Magnetic Resonance Imaging (FMRI), participants (n = 23 healthy humans; 14 female) anticipated and watched videos involving affiliative (tenderness, erotic desire, and awe) and nonaffiliative (i.e., food) rewards, as well as neutral scenes. On the one hand, anticipation of both affiliative and nonaffiliative rewards increased activity in the NAcc, anterior insula, and supplementary motor cortex, but activity in the amygdala and the ventromedial prefrontal cortex (vmPFC) increased in response to reward outcomes. On the other hand, affiliative rewards more specifically increased activity in the septo-hypothalamic area. Moreover, NAcc activity during anticipation correlated with positive arousal for all rewards, whereas septo-hypothalamic activity during the outcome correlated with positive arousal and motivation for subsequent re-exposure only for affiliative rewards. Together, these findings implicate a general appetitive response in the NAcc to different types of rewards but suggests a more specific response in the septo-hypothalamic region in response to affiliative rewards outcomes. This work also presents a new task for distinguishing between neural responses to affiliative and non-affiliative rewards.

Brain Activity Foreshadows Stock Price Dynamics.

Successful investing is challenging since stock prices are difficult to consistently forecast. Recent neuroimaging evidence suggests, however, that activity in brain regions associated with anticipatory affect may not only predict individual choice, but also forecast aggregate behavior out-of-sample. Thus, in two experiments, we specifically tested whether anticipatory affective brain activity in healthy humans could forecast aggregate changes in stock prices. Using functional magnetic resonance imaging, we found in a first experiment (n = 34, 6 females; 140 trials/subject) that nucleus accumbens activity forecast stock price direction, whereas anterior insula (AIns) activity forecast stock price inflections. In a second preregistered replication experiment (n = 39, 7 females) that included different subjects and stocks, AIns activity still forecast stock price inflections. Importantly, AIns activity forecast stock price movement even when choice behavior and conventional stock indicators did not (e.g., previous stock price movements), and classifier analysis indicated that forecasts based on brain activity should generalize to other markets. By demonstrating that AIns activity might serve as a leading indicator of stock price inflections, these findings imply that neural activity associated with anticipatory affect may extend to forecasting aggregate choice in dynamic and competitive environments such as stock markets.SIGNIFICANCE STATEMENT Many try but fail to consistently forecast changes in stock prices. New evidence, however, suggests that anticipatory affective brain activity may not only predict individual choice, but also may forecast aggregate choice. Assuming that stock prices index collective choice, we tested whether brain activity sampled during the assessment of stock prices could forecast subsequent changes in the prices of those stocks. In two neuroimaging experiments, a combination of previous stock price movements and brain activity in a region implicated in processing uncertainty and arousal forecast next-day stock price changes-even when behavior did not. These findings challenge traditional assumptions of market efficiency by implying that neuroimaging data might reveal "hidden information" capable of foreshadowing stock price dynamics.

White-matter tract connecting anterior insula to nucleus accumbens predicts greater future motivation in adolescents.

The motivation to approach or avoid incentives can change during adolescence. Advances in neuroimaging allow researchers to characterize specific brain circuits that underlie these developmental changes. Whereas activity in the nucleus accumbens (NAcc) can predict approach toward incentive gain, activity in anterior insula (AIns) is associated with avoidance of incentive loss. Recent research characterized the structural white-matter tract connecting the two brain regions, but the tract has neither been characterized in adolescence nor linked to functional activity during incentive anticipation. In this study, we collected diffusion MRI and characterized the tract connecting the AIns to the NAcc for the first time in early adolescents. We then measured NAcc functional activity during a monetary incentive delay task and found that structural coherence of the AIns-NAcc tract is correlated with decreased functional activity at the NAcc terminal of the tract during anticipation of no incentives. In adolescents who completed an assessment 2 years later, we found that AIns-NAcc tract coherence could predict greater future self-reported motivation, and that NAcc functional activity could statistically mediate this association. Together, the findings establish links from brain structure to function to future motivation and provide targets to study the reciprocal development of brain structure and function.

Medial forebrain bundle structure is linked to human impulsivity.

Comparative research indicates that projections from midbrain dopamine nuclei [including the ventral tegmental area (VTA)] to the ventral striatum [including the nucleus accumbens (NAcc)] critically support motivated behavior. Using diffusion-weighted imaging and probabilistic tractography in humans, we characterized the trajectory and structure of two tracts connecting the VTA and NAcc, as well as others connecting the substantia nigra and dorsal striatum. Decreased structural coherence of an inferior VTA-NAcc tract was primarily and replicably associated with increased trait impulsivity and also distinguished individuals with a stimulant use disorder from healthy controls. These findings suggest that decreased coherence of the inferior VTA-NAcc tract is associated with increased impulsivity in humans and identify a previously uncharacterized structural target for diagnosing disorders marked by impulsivity.

Brain-Responsive Neurostimulation for Loss of Control Eating: Early Feasibility Study.

BACKGROUND: Loss of control (LOC) is a pervasive feature of binge eating, which contributes significantly to the growing epidemic of obesity; approximately 80 million US adults are obese. Brain-responsive neurostimulation guided by the delta band was previously found to block binge-eating behavior in mice. Following novel preclinical work and a human case study demonstrating an association between the delta band and reward anticipation, the US Food and Drug Administration approved an Investigational Device Exemption for a first-in-human study. OBJECTIVE: To assess feasibility, safety, and nonfutility of brain-responsive neurostimulation for LOC eating in treatment-refractory obesity. METHODS: This is a single-site, early feasibility study with a randomized, single-blinded, staggered-onset design. Six subjects will undergo bilateral brain-responsive neurostimulation of the nucleus accumbens for LOC eating using the RNS® System (NeuroPace Inc). Eligible participants must have treatment-refractory obesity with body mass index ≥ 45 kg/m2. Electrophysiological signals of LOC will be characterized using real-time recording capabilities coupled with synchronized video monitoring. Effects on other eating disorder pathology, mood, neuropsychological profile, metabolic syndrome, and nutrition will also be assessed. EXPECTED OUTCOMES: Safety/feasibility of brain-responsive neurostimulation of the nucleus accumbens will be examined. The primary success criterion is a decrease of ≥1 LOC eating episode/week based on a 28-d average in ≥50% of subjects after 6 mo of responsive neurostimulation. DISCUSSION: This study is the first to use brain-responsive neurostimulation for obesity; this approach represents a paradigm shift for intractable mental health disorders.

Brain activity forecasts video engagement in an internet attention market.

The growth of the internet has spawned new "attention markets," in which people devote increasing amounts of time to consuming online content, but the neurobehavioral mechanisms that drive engagement in these markets have yet to be elucidated. We used functional MRI (FMRI) to examine whether individuals' neural responses to videos could predict their choices to start and stop watching videos as well as whether group brain activity could forecast aggregate video view frequency and duration out of sample on the internet (i.e., on youtube.com). Brain activity during video onset predicted individual choice in several regions (i.e., increased activity in the nucleus accumbens [NAcc] and medial prefrontal cortex [MPFC] as well as decreased activity in the anterior insula [AIns]). Group activity during video onset in only a subset of these regions, however, forecasted both aggregate view frequency and duration (i.e., increased NAcc and decreased AIns)-and did so above and beyond conventional measures. These findings extend neuroforecasting theory and tools by revealing that activity in brain regions implicated in anticipatory affect at the onset of video viewing (but not initial choice) can forecast time allocation out of sample in an internet attention market.