Spatial variation of changes in test-retest reliability of functional connectivity after global signal regression: The effect of considering hemodynamic delay.

Global signal regression (GSR) is a controversial analysis method, since its removal of signal has been observed to reduce the reliability of functional connectivity estimates. Here, we used test-retest reliability to characterize potential differences in spatial patterns between conventional, static GSR (sGSR) and a novel dynamic form of GSR (dGSR). In contrast with sGSR, dGSR models the global signal at a time delay to correct for blood arrival time. Thus, dGSR accounts for greater variation in global signal, removes blood-flow-related nuisance signal, and leaves higher quality neuronal signal remaining. We used intraclass correlation coefficients (ICCs) to estimate the reliability of functional connectivity in 462 healthy controls from the Human Connectome Project. We tested across two factors: denoising method used (control, sGSR, and dGSR), and interacquisition interval (between days, or within session while varying phase encoding direction). Reliability was estimated regionally to identify topographic patterns for each condition. sGSR and dGSR provided global reductions in reliability compared with the non-GSR control. Test-retest reliability was highest in the frontoparietal and default mode regions, and lowest in sensorimotor cortex for all conditions. dGSR provides more effective denoising in regions where both strategies greatly reduce reliability. Both GSR methods substantially reduced test-retest reliability, which was most evident in brain regions that had low reliability prior to denoising. These findings suggest that reliability of interregional correlation is likely inflated by the global signal, which is thought to primarily reflect dynamic blood flow.

Brain and cortisol responses to smoking cues are linked in tobacco-smoking individuals.

Cues associated with smoking can induce relapse, which is likely driven by cue-induced neurobiological and physiological mechanisms. For instance, greater relapse vulnerability is associated with increases in cue-induced insula activation and heightened cortisol concentrations. Determining if there is a link between such cue-induced responses is critical given the need for biomarkers that can be easily measured in clinical settings and used to drive targeted treatment. Further, comprehensively characterising biological reactions to cues promises to aid in the development of therapies that address this specific relapse risk factor. To determine whether brain and cortisol responses to smoking cues are linked, this study recruited 27 nicotine-dependent tobacco-smoking individuals and acquired whole-brain functional activation during a cue reactivity task; salivary cortisol was measured before and after scanning. The results showed that increases in blood-oxygen-level-dependent activation in the right anterior insula and right dorsolateral prefrontal cortex (DLPFC) when viewing smoking versus neutral cues were positively correlated with a post-scan rise in salivary cortisol concentrations. These brain regions have been previously implicated in substance use disorders for their role in salience, interoception and executive processes. These findings show that those who have a rise in cortisol following smoking cue exposure also have a related rise in cue-induced brain reactivity, in brain regions previously linked with heightened relapse vulnerability. This is clinically relevant as measuring cue-induced cortisol responses is a more accessible proxy for assessing the engagement of cue-induced neurobiological processes associated with the maintenance of nicotine dependence.

Dynamic functioning of transient resting-state coactivation networks in the Human Connectome Project.

Resting-state analyses evaluating large-scale brain networks have largely focused on static correlations in brain activity over extended time periods, however emerging approaches capture time-varying or dynamic patterns of transient functional networks. In light of these new approaches, there is a need to classify common transient network states (TNS) in terms of their spatial and dynamic properties. To fill this gap, two independent resting state scans collected in 462 healthy adults from the Human Connectome Project were evaluated using coactivation pattern analysis to identify (eight) TNS that recurred across participants and over time. These TNS spatially overlapped with prototypical resting state networks, but also diverged in notable ways. In particular, analyses revealed three TNS that shared cortical midline overlap with the default mode network (DMN), but these "complex" DMN states also encompassed distinct regions that fall beyond the prototypical DMN, suggesting that the DMN defined using static methods may represent the average of distinct complex-DMN states. Of note, dwell time was higher in "complex" DMN states, challenging the idea that the prototypical DMN, as a single unit, is the dominant resting-state network as typically defined by static resting state methods. In comparing the two resting state scans, we also found high reliability in the spatial organization and dynamic activities of network states involving DMN or sensorimotor regions. Future work will determine whether these TNS defined by coactivation patterns are in other samples, and are linked to fundamental cognitive properties.

Clinical Correlates of Smoking Status in Men and Women with Opioid Use Disorder.

Background: Smoking is highly prevalent in people with opioid use disorder (OUD) and is a significant contributor to morbidity and mortality in this population. However, little is known about the differences between those with OUD who do and do not smoke cigarettes. Objectives: Our aim was to investigate differences between treatment-seeking adults with OUD who did and did not smoke. Methods: Participants (N = 568; 30% female) completed a battery of self-report questionnaires including measures of current smoking status and number of cigarettes smoked per day as well as measures of clinical characteristics (e.g. craving, anxiety). Results: Of the total sample, 77% were current smokers. Multivariable logistic regression identified heroin use (OR = 2.20, 95% CI = 1.38, 3.53) and younger age (OR = 0.97, 95% CI = 0.95, 0.997) as strong correlates of smoking status; other characteristics were not significant. Older age and opioid craving were associated with more cigarettes smoked per day. Notably, these patterns differed for males and females; opioid craving (B = 0.62, SEB = 0.24) was associated with the number of cigarettes smoked among men, and anxiety (B = 0.39, SEB = 0.19) was associated with the number of cigarettes smoked among women. Conclusion: Adults with OUD who used heroin in the past month were more likely to be current smokers. No sex differences were observed in likelihood of smoking; however, the predictors of smoking status and severity differed between men and women.

Nicotine Increases Activation to Anticipatory Valence Cues in Anterior Insula and Striatum.

Introduction: Smoking is associated with significant morbidity and mortality. Understanding the neurobiology of the rewarding effects of nicotine promises to aid treatment development for nicotine dependence. Through its actions on mesolimbic dopaminergic systems, nicotine engenders enhanced responses to drug-related cues signaling rewards, a mechanism hypothesized to underlie the development and maintenance of nicotine addiction. Methods: We evaluated the effects of acute nicotine on neural responses to anticipatory cues signaling (nondrug) monetary reward or loss among 11 nonsmokers who had no prior history of tobacco smoking. In a double-blind, crossover design, participants completed study procedures while wearing nicotine or placebo patches at least 1 week apart. In each drug condition, participants underwent functional magnetic resonance imaging while performing the monetary incentive delay task and performed a probabilistic monetary reward task, probing reward responsiveness as measured by response bias toward a more frequently rewarded stimulus. Results: Nicotine administration was associated with enhanced activation, compared with placebo, of right fronto-anterior insular cortex and striatal regions in response to cues predicting possible rewards or losses and to dorsal anterior cingulate for rewards. Response bias toward rewarded stimuli correlated positively with insular activation to anticipatory cues. Conclusion: Nicotinic enhancement of monetary reward-related brain activation in the insula and striatum in nonsmokers dissociated acute effects of nicotine from effects on reward processing due to chronic smoking. Reward responsiveness predicted a greater nicotinic effect on insular activation to salient stimuli. Implications: Previous research demonstrates that nicotine enhances anticipatory responses to rewards in regions targeted by midbrain dopaminergic systems. The current study provides evidence that nicotine also enhances responses to rewards and losses in the anterior insula. A previous study found enhanced insular activation to rewards and losses in smokers and ex-smokers, a finding that could be due to nicotine sensitization or factors related to current or past smoking. Our finding of enhanced anterior insula response after acute administration of nicotine in nonsmokers provides support for nicotine-induced sensitization of insular response to rewards and losses.

Association Between Reward Reactivity and Drug Use Severity is Substance Dependent: Preliminary Evidence From the Human Connectome Project.

INTRODUCTION: Blunted nucleus accumbens (NAc) reactivity to reward is common across drug users. One theory is that individuals abuse substances due to this reward deficit. However, whether there is a relationship between the amount an individual uses and the severity of NAc dysfunction is unclear. It also is possible that such a relationship is substance specific, as nicotine transiently increases reward system sensitivity while alcohol, another commonly used substance, does not. As smokers may use nicotine to bolster NAc reward function, we hypothesize that NAc reactivity to reward will be related to volume of cigarette use, but not volume of alcohol use. METHODS: A functional magnetic resonance imaging incentive-processing task collected by the Human Connectome Project was assessed in a cohort of tobacco smokers who reported smoking between 5-20 cigarettes/day and a cohort of alcohol users who reported drinking 7-25 drinks/wk. Number of cigarettes/day and drinks/wk were correlated with right and left NAc reactivity to the receipt of a monetary reward relative to baseline. RESULTS: Individuals who smoke greater numbers of cigarettes/day showed lower right NAc reactivity to reward (r = 0.853, p ≤ .001). Left NAc reactivity was not correlated with cigarettes/day. No association was found with drinks/wk. CONCLUSIONS: A negative association was found between NAc reactivity to reward and cigarettes/day, but not alcohol drinks/wk. Given nicotine's unique ability to increase sensitivity to rewards, these findings suggest that individuals who smoke more cigarettes/day may be compensating for more dysfunctional NAc reward reactivity. IMPLICATIONS: The present study demonstrates that a relationship between NAc reactivity to nondrug reward and volume of substance use is present in nicotine but not alcohol use. While prior work has implicated dysfunctional reward processing in addictions, these findings clarify a substance-specific role that blunted reward function has in determining patterns of use among chronic users.

Salience and Default Mode Network Coupling Predicts Cognition in Aging and Parkinson's Disease.

OBJECTIVES: Cognitive impairment is common in Parkinson's disease (PD). Three neurocognitive networks support efficient cognition: the salience network, the default mode network, and the central executive network. The salience network is thought to switch between activating and deactivating the default mode and central executive networks. Anti-correlated interactions between the salience and default mode networks in particular are necessary for efficient cognition. Our previous work demonstrated altered functional coupling between the neurocognitive networks in non-demented individuals with PD compared to age-matched control participants. Here, we aim to identify associations between cognition and functional coupling between these neurocognitive networks in the same group of participants. METHODS: We investigated the extent to which intrinsic functional coupling among these neurocognitive networks is related to cognitive performance across three neuropsychological domains: executive functioning, psychomotor speed, and verbal memory. Twenty-four non-demented individuals with mild to moderate PD and 20 control participants were scanned at rest and evaluated on three neuropsychological domains. RESULTS: PD participants were impaired on tests from all three domains compared to control participants. Our imaging results demonstrated that successful cognition across healthy aging and Parkinson's disease participants was related to anti-correlated coupling between the salience and default mode networks. Individuals with poorer performance scores across groups demonstrated more positive salience network/default-mode network coupling. CONCLUSIONS: Successful cognition relies on healthy coupling between the salience and default mode networks, which may become dysfunctional in PD. These results can help inform non-pharmacological interventions (repetitive transcranial magnetic stimulation) targeting these specific networks before they become vulnerable in early stages of Parkinson's disease.

Default Mode Network Functional Reorganization During Early Abstinence in Polysubstance-Using Emerging Adults Treated for Opioid Dependence.

This study examined default mode network connectivity within the first 30 days of abstinence in emerging adults entering treatment for opioid dependence. There were significant associations between abstinence duration and coupling strength with brain regions within and outside of the network.

Memory retrieval of smoking-related images induce greater insula activation as revealed by an fMRI-based delayed matching to sample task.

Nicotine dependence is a chronic and difficult to treat disorder. While environmental stimuli associated with smoking precipitate craving and relapse, it is unknown whether smoking cues are cognitively processed differently than neutral stimuli. To evaluate working memory differences between smoking-related and neutral stimuli, we conducted a delay-match-to-sample (DMS) task concurrently with functional magnetic resonance imaging (fMRI) in nicotine-dependent participants. The DMS task evaluates brain activation during the encoding, maintenance and retrieval phases of working memory. Smoking images induced significantly more subjective craving, and greater midline cortical activation during encoding in comparison to neutral stimuli that were similar in content yet lacked a smoking component. The insula, which is involved in maintaining nicotine dependence, was active during the successful retrieval of previously viewed smoking versus neutral images. In contrast, neutral images required more prefrontal cortex-mediated active maintenance during the maintenance period. These findings indicate that distinct brain regions are involved in the different phases of working memory for smoking-related versus neutral images. Importantly, the results implicate the insula in the retrieval of smoking-related stimuli, which is relevant given the insula's emerging role in addiction.

Brain-wide functional connectivity artifactually inflates throughout functional magnetic resonance imaging scans.

Functional magnetic resonance imaging (fMRI) is a central tool for investigating human brain function, organization and disease. Here, we show that fMRI-based estimates of functional brain connectivity artifactually inflate at spatially heterogeneous rates during resting-state and task-based scans. This produces false positive connection strength changes and spatial distortion of brain connectivity maps. We demonstrate that this artefact is driven by temporal inflation of the non-neuronal, systemic low-frequency oscillation (sLFO) blood flow signal during fMRI scanning and is not addressed by standard denoising procedures. We provide evidence that sLFO inflation reflects perturbations in cerebral blood flow by respiration and heart rate changes that accompany diminishing arousal during scanning, although the mechanisms of this pathway are uncertain. Finally, we show that adding a specialized sLFO denoising procedure to fMRI processing pipelines mitigates the artifactual inflation of functional connectivity, enhancing the validity and within-scan reliability of fMRI findings.

Data-driven connectivity profiles relate to smoking cessation outcomes.

At a group level, nicotine dependence is linked to differences in resting-state functional connectivity (rs-FC) within and between three large-scale brain networks: the salience network (SN), default mode network (DMN), and frontoparietal network (FPN). Yet, individuals may display distinct patterns of rs-FC that impact treatment outcomes. This study used a data-driven approach, Group Iterative Multiple Model Estimation (GIMME), to characterize shared and person-specific rs-FC features linked with clinically-relevant treatment outcomes. 49 nicotine-dependent adults completed a resting-state fMRI scan prior to a two-week smoking cessation attempt. We used GIMME to identify group, subgroup, and individual-level networks of SN, DMN, and FPN connectivity. Regression models assessed whether within- and between-network connectivity of individual rs-FC models was associated with baseline cue-induced craving, and craving and use of regular cigarettes (i.e., "slips") during cessation. As a group, participants displayed shared patterns of connectivity within all three networks, and connectivity between the SN-FPN and DMN-SN. However, there was substantial heterogeneity across individuals. Individuals with greater within-network SN connectivity experienced more slips during treatment, while individuals with greater DMN-FPN connectivity experienced fewer slips. Individuals with more anticorrelated DMN-SN connectivity reported lower craving during treatment, while SN-FPN connectivity was linked to higher craving. In conclusion, in nicotine-dependent adults, GIMME identified substantial heterogeneity within and between the large-scale brain networks. Individuals with greater SN connectivity may be at increased risk for relapse during treatment, while a greater positive DMN-FPN and negative DMN-SN connectivity may be protective for individuals during smoking cessation treatment.

Childhood Trauma, Emotional Awareness, and Neural Correlates of Long-Term Nicotine Smoking.

Importance: Temporal dynamic measures provide insight into the neurobiological properties of nicotine use. It is critical to determine whether brain-based measures are associated with substance use risk factors, such as childhood trauma-related emotion dysregulation. Objective: To assess temporal dynamic differences based on smoking status and examine the associations between childhood trauma, alexithymia, nicotine smoking, and default mode network (DMN) states. Design, Setting, and Participants: This cross-sectional study was conducted in the Baltimore, Maryland, area at the National Institute on Drug Abuse. Participants included individuals aged 18 to 65 years who smoked nicotine long term and matched controls with no co-occurring substance use or psychiatric disorders. Participants were enrolled from August 8, 2013, to August 9, 2022. Analysis was conducted from August 2022 to July 2023. Exposure: Long-term nicotine smoking. Main Outcomes and Measures: The main outcome was temporal dynamic differences based on smoking status. Coactivation pattern analysis was conducted based on 16-minute resting-state functional magnetic resonance imaging; total time in, persistence of, and frequency of transitions into states were evaluated. The associations between childhood trauma (Childhood Trauma Questionnaire), alexithymia (20-item Toronto Alexithymia Scale), and DMN temporal dynamics were assessed. Results: The sample included 204 participants (102 individuals who smoked nicotine and 102 control individuals) with a mean (SD) age of 37.53 (10.64) years (109 [53.4%] male). Compared with controls, individuals who smoked nicotine spent more time in the frontoinsular DMN (FI-DMN) state (mean difference, 25.63 seconds; 95% CI, 8.05-43.20 seconds; η2p = 0.04; P = .004 after Bonferroni correction). In those who smoked nicotine, greater alexithymia was associated with less time spent in the FI-DMN state (r, -0.26; 95% CI, -0.44 to -0.07; P = .007). In a moderated mediation analysis, alexithymia mediated the association between childhood trauma and time spent in the FI-DMN state only in individuals who smoked nicotine (c' = -0.24; 95% CI, -0.58 to -0.03; P = .02). Conclusions and Relevance: Compared with controls, individuals who smoked nicotine spent more time in the FI-DMN state. Among those who smoked nicotine, childhood trauma-related alexithymia was associated with less time spent in the FI-DMN state, indicating that considering trauma-related factors may reveal alternative neurobiological underpinnings of substance use. These data may aid in reconciling contradictory findings in prior literature regarding the role of FI-DMN regions in substance use.

Use of Tobacco Products and Suicide Attempts Among Elementary School-Aged Children.

Importance: The use of tobacco products, including e-cigarettes and vaping, has rapidly increased among children. However, despite consistent associations found between smoking cigarettes and suicidal behaviors among adolescents and adults, there are limited data on associations between emerging tobacco products and suicidal behaviors, especially among preadolescent children. Objective: To examine whether the use of tobacco products is associated with nonsuicidal self-injury (NSSI), suicidal ideation (SI), and suicide attempts (SAs) among preadolescent children. Design, Setting, and Participants: This cohort study, conducted from September 1, 2022, to September 5, 2023, included participants in the Adolescent Brain Cognitive Development study, a population-based cohort of 11 868 US children enrolled at 9 and 10 years of age. The cross-sectional investigation focused on 3-year periods starting from the baseline to year 2 of follow-up. Statistical analysis was performed from October 1, 2022, to June 30, 2023. Main Outcomes and Measures: Children's use of tobacco products was assessed based on youth reports, including lifetime experiences of various nicotine-related products, supplemented with hair toxicologic tests. Main outcomes were children's lifetime experiences of NSSI, SI, and SAs, assessed using the K-SADS-5 (Kiddie Schedule for Affective Disorders and Schizophrenia for the DSM-5). Multivariate logistic regression was conducted to examine the associations of the use of tobacco products with NSSI, SI, and SAs among the study participants. Sociodemographic, familial, and children's behavioral, temperamental, and clinical outcomes were adjusted in the analyses. Results: Of 8988 unrelated study participants (median age, 9.8 years [range, 8.9-11.0 years]; 4301 girls [47.9%]), 101 children (1.1%) and 151 children (1.7%) acknowledged lifetime use of tobacco products at baseline and at 18-month follow-up, respectively. After accounting for various suicide risk factors and potential confounders, children reporting use of tobacco products were at a 3 to 5 times increased risk of SAs (baseline: n = 153 [adjusted odds ratio (OR), 4.67; 95% CI, 2.35-9.28; false discovery rate (FDR)-corrected P < .001]; year 1: n = 227 [adjusted OR, 4.25; 95% CI, 2.33-7.74; FDR-corrected P < .001]; and year 2: n = 321 [adjusted OR, 2.85; 95% CI, 1.58-5.13; FDR-corrected P = .001]). Of all facets of impulsivity measures that were significant correlates of use of tobacco products, negative urgency was the only independent risk factor for SAs (adjusted OR, 1.52 [95% CI, 1.31-1.78]; FDR-corrected P < .001). In contrast, children's alcohol, cannabis, and prescription drug use were not associated with SAs. Conclusions and Relevance: This study of US children suggests that the increased risk of SAs, consistently reported for adolescents and adults who smoke cigarettes, extends to a range of emerging tobacco products and manifests among elementary school-aged children. Further investigations are imperative to clarify the underlying mechanisms and to implement effective preventive policies for children.

Connectome-based Brain Marker Moderates the Relationship between Childhood Adversity and Transdiagnostic Psychopathology during Early Adolescence.

Importance: Identifying brain-based markers of resiliency that reliably predict who is and is not at elevated risk for developing psychopathology among children who experience adverse childhood experiences (ACEs) is important for improving our mechanistic understanding of these etiological links between child adversity and psychopathology and guiding precision medicine and prevention efforts for reducing psychiatric impact of ACEs. Objective: To examine associations between ACEs and transdiagnostic psychopathology during the transition from preadolescence to early adolescence and test whether these associations are moderated by a hypothesized resilience factor, a previously identified connectome variate (CV) that is associated with higher cognitive function and lower psychopathology. Design Setting and Participants: This study was conducted in a longitudinal design based on multicenter data from a community cohort of U.S. youth aged of 9-11 at baseline, who participated in the Adolescent Brain Cognitive Development (ABCD) study (N=7,382 at baseline and 6,813 at 2-year follow-up). Linear regression models and moderation analyses were used to characterize concurrent and prospective associations between lifetime ACEs and number of DSM-5 psychiatric disorders (indexing transdiagnostic psychopathology) and to determine if individual variations in these associations were moderated by the CV derived from resting-state fMRI at baseline. Main Outcomes and Measures: Cumulative number of current DSM-5 psychiatric disorders assessed using the computerized self-admin version Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-5) and lifetime ACEs assessed from child and parent reports at baseline (9-10 years) and 2-year-follow-up (11-12 years). Results: ACE total scores correlated positively with the cumulative number of current DSM-5 psychiatric disorders at both baseline (r =.258, p < .001) and 2-year follow-up (r =.257, p < .001). The baseline CV score moderated the ACE-disorder associations at baseline (B = -0.021, p < .001) and at 2-year follow-up (B = -0.018, p = .008), as well as the association between the changes in ACE and in the number of disorders from baseline to year 2 (B = -0.012, p = .045). Post-hoc analyses further showed that the moderation effect of CV on ACE-psychopathology associations was specific to the threat-related ACEs and to female youth. Conclusions and Relevance: These findings provide preliminary evidence for a connectome-based resiliency marker and suggest that functional connectivity strength in a broad system including frontal-parietal cortices and subcortical nuclei relevant to cognitive control may protect preadolescents who have experienced lifetime ACEs--especially females and those experiencing threat-related ACEs--from developing transdiagnostic psychopathology.

Brain-wide functional connectivity artifactually inflates throughout fMRI scans: a problem and solution.

The fMRI blood oxygen level-dependent (BOLD) signal is a mainstay of neuroimaging assessment of neuronal activity and functional connectivity in vivo. Thus, a chief priority is maximizing this signal's reliability and validity. To this end, the fMRI community has invested considerable effort into optimizing both experimental designs and physiological denoising procedures to improve the accuracy, across-scan reproducibility, and subject discriminability of BOLD-derived metrics like functional connectivity. Despite these advances, we discover that a substantial and ubiquitous defect remains in fMRI datasets: functional connectivity throughout the brain artifactually inflates during the course of fMRI scans - by an average of more than 70% in 15 minutes of scan time - at spatially heterogeneous rates, producing both spatial and temporal distortion of brain connectivity maps. We provide evidence that this inflation is driven by a previously unrecognized time-dependent increase of non-neuronal, systemic low-frequency oscillation (sLFO) blood flow signal during fMRI scanning. This signal is not removed by standard denoising procedures such as independent component analysis (ICA). However, we demonstrate that a specialized sLFO denoising procedure - Regressor Interpolation at Progressive Time Delays (RIPTiDe) - can be added to standard denoising pipelines to significantly attenuate functional connectivity inflation. We confirm the presence of sLFO-driven functional connectivity inflation in multiple independent fMRI datasets - including the Human Connectome Project - as well as across resting-state, task, and sleep-state conditions, and demonstrate its potential to produce false positive findings. Collectively, we present evidence for a previously unknown physiological phenomenon that spatiotemporally distorts estimates of brain connectivity in human fMRI datasets, and present a solution for mitigating this artifact.

Enhanced decision-making in nicotine dependent individuals who abstain: A computational analysis using Hierarchical Drift Diffusion Modeling.

BACKGROUND: Variability in decision-making capacity and reward responsiveness may underlie differences in the ability to abstain from smoking. Computational modeling of choice behavior, as with the Hierarchical Drift Diffusion Model (HDDM), can help dissociate reward responsiveness from underlying components of decision-making. Here we used the HDDM to identify which decision-making or reward-related parameters, extracted from data acquired in a reward processing task, contributed to the ability of people who smoke that are not seeking treatment to abstain from cigarettes during a laboratory task. METHODS: 80 adults who smoke cigarettes completed the Probabilistic Reward Task (PRT) - a signal detection task with a differential reinforcement schedule - following smoking as usual, and the Relapse Analogue Task (RAT) - a task in which participants could earn money for delaying smoking up to 50min - after a period of overnight abstinence. Two cohorts were defined by the RAT; those who waited either 0-min (n=36) or the full 50-min (n=44) before smoking. RESULTS: PRT signal detection metrics indicated all subjects learned the task contingencies, with no differences in response bias or discriminability between the two groups. However, HDDM analyses indicated faster drift rates in 50-min vs. 0-min waiters. CONCLUSIONS: Relative to those who did not abstain, computational modeling indicated that people who abstained from smoking for 50min showed faster evidence accumulation during reward-based decision-making. These results highlight the importance of decision-making mechanisms to smoking abstinence, and suggest that focusing on the evidence accumulation process may yield new targets for treatment.

Positive reinforcement training in squirrel monkeys using clicker training.

Nonhuman primates in research environments experience regular stressors that have the potential to alter physiology and brain function, which in turn can confound some types of research studies. Operant conditioning techniques such as positive reinforcement training (PRT), which teaches animals to voluntarily perform desired behaviors, can be applied to improve behavior and reactivity. PRT has been used to train rhesus macaques, marmosets, and several other nonhuman primate species. To our knowledge, the method has yet to be used to train squirrel monkeys to perform complex tasks. Accordingly, we sought to establish whether PRT, utilizing a hand-box clicker (which emits a click sound that acts as the conditioned reinforcer), could be used to train adult male squirrel monkeys (Saimiri boliviensis, N = 14). We developed and implemented a training regimen to elicit voluntary participation in routine husbandry, animal transport, and injection procedures. Our secondary goal was to quantify the training time needed to achieve positive results. Squirrel monkeys readily learned the connection between the conditioned reinforcer (the clicker) and the positive reinforcer (food). They rapidly developed proficiency on four tasks of increasing difficulty: target touching, hand sitting, restraint training, and injection training. All subjects mastered target touching behavior within 2 weeks. Ten of 14 subjects (71%) mastered all tasks in 59.2 ± 2.6 days (range: 50-70 days). In trained subjects, it now takes about 1.25 min per monkey to weigh and administer an intramuscular injection, one-third of the time it took before training. From these data, we conclude that clicker box PRT can be successfully learned by a majority of squirrel monkeys within 2 months and that trained subjects can be managed more efficiently. These findings warrant future studies to determine whether PRT may be useful in reducing stress-induced experimental confounds in studies involving squirrel monkeys.

Alcohol- and non-alcohol-related interference: An fMRI study of treatment-seeking adults with alcohol use disorder.

BACKGROUND: Individuals with alcohol use disorder (AUD) have difficulty diverting attention away from alcohol-related stimuli and towards non-alcohol-related goals (i.e., alcohol-related attention interference). It remains unclear whether regulatory brain function differs during alcohol and non-alcohol-related interference. This study compares brain reactivity during the alcohol and classic Stroop and whether such brain function relates to AUD severity. METHODS: 46 participants with AUD completed alcohol and classic color-word Stroop tasks during fMRI. Brain activity was compared during alcohol and classic Stroop interference in the rostral and dorsal anterior cingulate cortices (rACC and dACC) and correlated with self-reported AUD severity. Exploratory whole-brain analyses were also conducted. RESULTS: Behavioral interference (i.e., slower reaction times) was observed during alcohol and classic Stroop. rACC activity was significantly higher during the alcohol > neutral contrast versus the incongruent > congruent contrast. dACC activity did not differ between the Stroop tasks. dACC activity during incongruent > congruent was positively associated with AUD severity. CONCLUSIONS: Activity in ACC subregions differed during alcohol and non-alcohol interference. Increased alcohol-related activity in the rACC, a region linked to emotional conflict resolution, suggests an interfering effect of self-relevant alcohol cues on non-alcohol-related processing. AUD severity was related to greater dACC reactivity during classic Stroop interference, suggesting that non-drug-related cognitive control impairments are more pronounced in those with more problematic alcohol use.

Evidence for Schizophrenia-Specific Pathophysiology of Nicotine Dependence.

Tobacco use is the top preventable cause of early mortality in schizophrenia. Over 60% of people with schizophrenia smoke, three times the general prevalence. The biological basis of this increased risk is not understood, and existing interventions do not target schizophrenia-specific pathology. We therefore used a connectome-wide analysis to identify schizophrenia-specific circuits of nicotine addiction. We reanalyzed data from two studies: In Cohort 1, 35 smokers (18 schizophrenia, 17 control) underwent resting-state fMRI and clinical characterization. A multivariate pattern analysis of whole-connectome data was used to identify the strongest links between cigarette use and functional connectivity. In Cohort 2, 12 schizophrenia participants and 12 controls were enrolled in a randomized, controlled crossover study of nicotine patch with resting-state fMRI. We correlated change in network functional connectivity with nicotine dose. In Cohort 1, the strongest (p < 0.001) correlate between connectivity and cigarette use was driven by individual variation in default mode network (DMN) topography. In individuals with greater daily cigarette consumption, we observed a pathological expansion of the DMN territory into the identified parieto-occipital region, while in individuals with lower daily cigarette consumption, this region was external to the DMN. This effect was entirely driven by schizophrenia participants. Given the relationship between DMN topography and nicotine use we observed in Cohort 1, we sought to directly test the impact of nicotine on this network using an independent second cohort. In Cohort 2, nicotine reduced DMN connectivity in a dose-dependent manner (R = -0.50; 95% CI -0.75 to -0.12, p < 0.05). In the placebo condition, schizophrenia subjects had hyperconnectivity compared to controls (p < 0.05). Nicotine administration normalized DMN hyperconnectivity in schizophrenia. We here provide direct evidence that the biological basis of nicotine dependence is different in schizophrenia and in non-schizophrenia populations. Our results suggest the high prevalence of nicotine use in schizophrenia may be an attempt to correct a network deficit known to interfere with cognition.

Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial.

Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials.