The Effects of Nicotine and Tobacco Use on Brain Reward Function: Interaction With Nicotine Dependence Severity.

INTRODUCTION: This study investigated the effects of nicotine/tobacco on neural activation during performance of a monetary incentive delay task. AIMS AND METHODS: Prior to each scan, nonsmokers received nicotine or placebo nasal spray, and smokers were smoking satiated or 24-hour withdrawn. During the scan, participants made timed responses to reward-related cues and received feedback. Parameter estimates from cue- and feedback-related activation in medial prefrontal regions and the nucleus accumbens were extracted and underwent within- and between-group analyses. Smokers' nicotine dependence severity was included as a continuous predictor variable for neural activation. RESULTS: Among smokers (n = 21), withdrawal decreased cue-related activation in the supplementary motor area and ventromedial prefrontal cortex, and the difference in activation (satiety > withdrawal) in these regions negatively correlated with nicotine dependence severity (Fagerström Test for Nicotine Dependence). Among nonsmokers (n = 22), nicotine increased the difference in nucleus accumbens activation between rewarded and nonrewarded feedback phases. Tobacco withdrawal and acute nicotine also had widespread effects on activation throughout the brain during the feedback phase. CONCLUSIONS: Acute nicotine in nonsmokers may have increased the salience of feedback information, but produced few effects on reward-related activation overall, perhaps reflecting nicotine's modest, indirect effects on reward processing. Conversely, tobacco withdrawal decreased activation compared with satiety, and this difference between conditions correlated with nicotine dependence severity. This suggests that as smokers become more dependent on nicotine, tobacco withdrawal has a more pronounced effect on reward processing. IMPLICATIONS: Relative to the acute effects of nicotine in nonsmokers, withdrawal from daily tobacco use had more significant effects on reward-related brain activation. This study suggests that the effects of tobacco withdrawal on reward-related brain function interact with subjects' level of nicotine dependence severity. These are potentially important sources of variability that could contribute to smoking cessation outcomes.

Nicotine Withdrawal Induces Neural Deficits in Reward Processing.

INTRODUCTION: Nicotine withdrawal reduces neurobiological responses to nonsmoking rewards. Insight into these reward deficits could inform the development of targeted interventions. This study examined the effect of withdrawal on neural and behavioral responses during a reward prediction task. METHODS: Smokers (N = 48) attended two laboratory sessions following overnight abstinence. Withdrawal was manipulated by having participants smoke three regular nicotine (0.6 mg yield; satiation) or very low nicotine (0.05 mg yield; withdrawal) cigarettes. Electrophysiological recordings of neural activity were obtained while participants completed a reward prediction task that involved viewing four combinations of predictive and reward-determining stimuli: (1) Unexpected Reward; (2) Predicted Reward; (3) Predicted Punishment; (4) Unexpected Punishment. The task evokes a medial frontal negativity that mimics the phasic pattern of dopaminergic firing in ventral tegmental regions associated with reward prediction errors. RESULTS: Nicotine withdrawal decreased the amplitude of the medial frontal negativity equally across all trial types (p < .001). Exploratory analyses indicated withdrawal increased time to initiate the next trial following unexpected punishment trials (p < .001) and response time on reward trials during withdrawal was positively related to nicotine dependence (p < .001). CONCLUSIONS: Nicotine withdrawal had equivocal impact across trial types, suggesting reward processing deficits are unlikely to stem from changes in phasic dopaminergic activity during prediction errors. Effects on tonic activity may be more pronounced. Pharmacological interventions directly targeting the dopamine system and behavioral interventions designed to increase reward motivation and responsiveness (eg, behavioral activation) may aid in mitigating withdrawal symptoms and potentially improving smoking cessation outcomes. IMPLICATIONS: Findings from this study indicate nicotine withdrawal impacts reward processing signals that are observable in smokers' neural activity. This may play a role in the subjective aversive experience of nicotine withdrawal and potentially contribute to smoking relapse. Interventions that address abnormal responding to both pleasant and unpleasant stimuli may be particularly effective for alleviating nicotine withdrawal.

The effects of nicotine and non-nicotine smoking factors on working memory and associated brain function.

Smoking abstinence impairs executive function, which may promote continued smoking behavior and relapse. The differential influence of nicotine and non-nicotine (i.e. sensory, motor) smoking factors and related neural substrates is not known. In a fully factorial, within-subjects design, 33 smokers underwent fMRI scanning following 24 hours of wearing a nicotine or placebo patch while smoking very low nicotine content cigarettes or remaining abstinent from smoking. During scanning, blood oxygenation level-dependent (BOLD) signal was acquired while participants performed a verbal N-back task. Following 24-hour placebo (versus nicotine) administration, accuracy on the N-back task was significantly worse and task-related BOLD signal lower in dorsomedial frontal cortex. These effects were observed irrespective of smoking. Our data provide novel evidence that abstinence-induced deficits in working memory and changes in underlying brain function are due in large part to abstinence from nicotine compared with non-nicotine factors. This work has implications both for designing interventions that target abstinence-induced cognitive deficits and for nicotine-reduction policy.

A randomized controlled trial of intermittent theta burst stimulation to the medial prefrontal cortex for tobacco use disorder: Clinical efficacy and safety.

OBJECTIVE: This study aimed to evaluate the clinical efficacy and safety of administering intermittent theta burst stimulation (iTBS) to the medial prefrontal cortex for tobacco use disorder. METHODS: A randomized sham-controlled trial was conducted, with 38 participants receiving 28 sessions of active (n=25) or sham (n=13) iTBS (2 sessions/day, 600 pulses/session, 110% resting motor threshold, AFz target) along with smoking cessation education (Forever Free © booklets) over 14 visits. Primary outcomes included self-reported cigarette consumption and abstinence, verified by urinary cotinine tests. Secondary outcomes included symptoms of tobacco use disorder, negative mood, and safety/tolerability. RESULTS: Both active and sham groups reported reduced cigarette consumption (ß = -0.12, p = 0.015), cigarette craving (ß = -0.16, p = 0.002), and tobacco withdrawal symptoms (ß = -0.05, p < 0.001). However, there were no significant time x group interaction effects for any measure. Similarly, the two groups had no significant differences in urinary cotinine-verified abstinence. Adverse events occurred with similar frequency in both groups. CONCLUSION: There were no differences in cigarette consumption between the active and sham iTBS groups, both groups decreased cigarette consumption similarly. Further research is needed to compare iTBS to standard high-frequency rTMS and explore the potential differences in efficacy. Despite limitations, this study contributes to experimental design considerations for TMS as a novel intervention for tobacco and other substance use disorders, emphasizing the need for a more comprehensive understanding of the stimulation parameters and target sites.

Smoking status affects cognitive, emotional and neural-connectivity response to distress-inducing auditory feedback.

BACKGROUND: An important motive for cigarette smoking and impediment to cessation success is the avoidance of affective distress. Low levels of distress tolerance have been linked to smoking behavior, cessation history, smoking characteristics, and risk of recurrence among people who smoke. A better understanding of the neural mechanisms underlying distress sensitivity could inform approaches to help reduce avoidance of affective distress during smoking cessation. Previously among healthy participants, low distress tolerance on an MRI version of the Paced Auditory Serial Addition Task (PASAT-M), which induces distress via negative auditory feedback, was associated with larger differences in task-based functional connectivity (TBFC) between the auditory seed region and the anterior insula. METHODS: Here, we tested differences in task performance and TBFC during affective distress among people who smoke (Smoke; n = 31) and people who quit smoking (Ex-smoke; n = 31). RESULTS: Smoke had poorer task accuracy and reported a steeper increase in negative mood from the easy to distress blocks. Smoke had a larger difference in connectivity (distress > easy condition) between the auditory seed region and the left inferior frontal gyrus and right anterior insula. Additionally, task accuracy positively correlated with the difference in connectivity (distress > easy condition) with the left inferior frontal gyrus and the right anterior insula among Smoke but not Ex-smoke. CONCLUSIONS: These results are consistent with the idea that people who smoke are more sensitive to cognitive-affective distress and that the inferior frontal gyrus and anterior insula play important roles in the regulation of distress.

Association of DNA methylation signatures with cognitive performance among smokers and ex-smokers.

INTRODUCTION: Alterations in DNA methylation profiles have been associated with cancer, and can be influenced by environmental factors such as smoking. A small but growing literature indicates there are reproducible and robust differences in methylation levels among smokers, never smokers, and ex-smokers. Here, we compared differences in salivary DNA methylation levels among current and ex-smokers (at least 2 years abstinent). METHODS: Smokers (n=26) and ex-smokers (n=30) provided detailed smoking histories, completed the Paced Auditory Serial Addition Test (PASAT), and submitted a saliva sample. Whole-genome DNA methylation from saliva was performed, and ANCOVA models and a receiver operating characteristic (ROC) curve were used for the differences between groups and the performance of significant CpG sites. RESULTS: After controlling for race, age, and gender, smokers had significantly lower methylation levels than ex-smokers in two CpG sites: cg05575921 (AHRR) and cg21566642 (ALPPL2). Based on the ROC analyses, both CpGs had strong classification potentials (cg05575921 AUC=0.97 and cg21566642 AUC=0.93) in differentiating smoking status. Across all subjects, the percent methylation of cg05575921 (AHRR) and cg21566642 (ALPPL2) positively correlated with the length of the last quit attempt (r=0.65 and 0.64, respectively, p<0.001) and PASAT accuracy (r=0.29 and 0.30, respectively, p<0.05). CONCLUSIONS: In spite of the small sample size and preliminary research, our results replicate previously reported differences in AHRR hypomethylation among smokers. Furthermore, we show that the duration of smoking abstinence is associated with a recovery of methylation in ex-smokers, which may be linked to a reduced risk of smoking-associated diseases. The association with cognitive performance suggests that the hypomethylation of AHRR in saliva may reflect systemic exposure to cigarette-related toxicants that negatively affect cognitive performance, and should be validated in larger studies.

Biochemical validation of self-reported electronic nicotine delivery system and tobacco heaviness of use.

Research on tobacco use disorder relies on a combination of self-reported use (e.g., cigarettes per day) and biochemical validation to quantify heaviness of use. However, electronic nicotine delivery system (ENDS) users may be unaware of how much they have vaped per day. The aim of this study was to test the relationship between self-reported heaviness of ENDS/tobacco use and nicotine biomarkers. Young adults (n = 30) who currently use ENDS and other tobacco products completed a detailed tobacco use history, timeline follow-back, and an ENDS topography session. We evaluated the self-reports of own-brand ENDS use and tested correlations to determine which self-report measures of own-brand use, and which self-reported measures of puff topography, had the strongest correlations with urine and/or blood biomarkers of nicotine use. Participants reported using a variety of different ENDS devices and had a range of usage. The sum of the self-reported number of occasions or hours of ENDS use, along with the number of cigarettes and other tobacco products used, over the past 24 hr was significantly correlated with plasma cotinine levels. Puff topography measures correlated with increased nicotine concentrations, although participants underestimated the number of puffs they took during the topography session. This study provides preliminary evidence that summing together the hours of ENDS use, or the number of occasions of ENDS use, in addition to the number of other tobacco products used (i.e., cigarettes) based on self-report may be an accurate method of quantification. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Analysis of Caregiver Burden Expressed in Social Media Discussions.

Almost 40% of US adults provide informal caregiving, yet research gaps remain around what burdens affect informal caregivers. This study uses a novel social media site, Reddit, to mine and better understand what online communities focus on as their caregiving burdens. These forums were accessed using an application programming interface, a machine learning classifier was developed to remove low information posts, and topic modeling was applied to the corpus. An expert panel summarized the forums' themes into ten categories. The largest theme extracted from Reddit's forums discussed the personal emotional toll of being a caregiver. This was followed by logistic issues while caregiving and caring for parents who have cancer. Smaller themes included approaches to end-of-life care, physical equipment needs when caregiving, and the use of wearables or technology to help monitor care recipients. The platform often discusses caregiving for parents which may reflect the age of Reddit's users. This study confirms that Reddit forums are used for caregivers to discuss the burdens associated with their role and the types of stress that can result from informal caregiving.

Multimodal smoking cessation treatment combining transcranial magnetic stimulation, cognitive behavioral therapy, and nicotine replacement therapy in veterans with posttraumatic stress disorder: A feasibility randomized controlled trial protocol.

Tobacco-related deaths exceed those resulting from homicides, suicides, motor vehicle accidence, alcohol consumption, illicit substance use, and acquired immunodeficiency syndrome (AIDS), combined. Amongst U.S. veterans, this trend is particularly concerning given that those suffering from posttraumatic stress disorder (PTSD)-about 11% of those receiving care from the Department of Veterans Affairs (VA)-have triple the risk of developing tobacco use disorder (TUD). The most efficacious strategies being used at the VA for smoking cessation only result in a 23% abstinence rate, and veterans with PTSD only achieve a 4.5% abstinence rate. Therefore, there is a critical need to develop more effective treatments for smoking cessation. Recent studies have revealed the insula as integrally involved in the neurocircuitry of TUD, specifically showing that individuals with brain lesions involving this region had drastically improved quit rates. Some of these studies show a probability of quitting up to 5 times greater compared to non-insula lesioned regions). Altered activity of the insula may be involved in the disruption of the salience network's (SN) connectivity to the executive control network (ECN), which compromises that patient's ability to switch between interoceptive states focused on cravings to executive and cognitive control. Thus, we propose a feasibility phase II randomized controlled trial (RCT) to study a patterned form of repetitive transcranial magnetic stimulation (rTMS), intermittent theta burst stimulation (iTBS), at 90% of the subject's resting motor threshold (rMT) applied over a region in the right post-central gyrus most functionally connected to the right posterior insula. We hypothesize that by increasing functional connectivity between the SN with the ECN to enhance executive control and by decreasing connectivity with the default mode network (DMN) to reduce interoceptive focus on withdrawal symptoms, we will improve smoking cessation outcomes. Fifty eligible veterans with comorbid TUD and PTSD will be randomly assigned to two conditions: active-iTBS + cognitive behavioral therapy (CBT) + nicotine replacement therapy (NRT) (n=25) or sham-iTBS + CBT + NRT (n=25). The primary outcome, feasibility, will be determined by achieving a recruitment of 50 participants and retention rate of 80%. The success of iTBS will be evaluated through self-reported nicotine use, cravings, withdrawal symptoms, and abstinence following quit date (confirmed by bioverification) along with evaluation for target engagement through neuroimaging changes, specifically connectivity differences between the insula and other regions of interest.

Cognition, Aryl Hydrocarbon Receptor Repressor Methylation, and Abstinence Duration-Associated Multimodal Brain Networks in Smoking and Long-Term Smoking Cessation.

Cigarette smoking and smoking cessation are associated with changes in cognition and DNA methylation; however, the neurobiological correlates of these effects have not been fully elucidated, especially in long-term cessation. Cognitive performance, percent methylation of the aryl hydrocarbon receptor repressor (AHRR) gene, and abstinence duration were used as references to supervise a multimodal fusion analysis of functional, structural, and diffusion magnetic resonance imaging (MRI) data, in order to identify associated brain networks in smokers and ex-smokers. Correlations among these networks and with smoking-related measures were performed. Cognition-, methylation-, and abstinence duration-associated networks discriminated between smokers and ex-smokers and correlated with differences in fractional amplitude of low frequency fluctuations (fALFF) values, gray matter volume (GMV), and fractional anisotropy (FA) values. Long-term smoking cessation was associated with more accurate cognitive performance, as well as lower fALFF and more GMV in the hippocampus complex. The methylation- and abstinence duration-associated networks positively correlated with smoking-related measures of abstinence duration and percent methylation, respectively, suggesting they are complementary measures. This analysis revealed structural and functional co-alterations linked to smoking abstinence and cognitive performance in brain regions including the insula, frontal gyri, and lingual gyri. Furthermore, AHRR methylation, a promising epigenetic biomarker of smoking recency, may provide an important complement to self-reported abstinence duration.

Attention-deficit/hyperactivity disorder and the explore/exploit trade-off.

The ability to maximize rewards and minimize the costs of obtaining them is vital to making advantageous explore/exploit decisions. Exploratory decisions are theorized to be greater among individuals with attention-deficit/hyperactivity disorder (ADHD), potentially due to deficient catecholamine transmission. Here, we examined the effects of ADHD status and methylphenidate, a common ADHD medication, on explore/exploit decisions using a 6-armed bandit task. We hypothesized that ADHD participants would make more exploratory decisions than controls, and that MPH would reduce group differences. On separate study days, adults with (n = 26) and without (n = 23) ADHD completed the bandit task at baseline, and after methylphenidate or placebo in counter-balanced order. Explore/exploit decisions were modeled using reinforcement learning algorithms. ADHD participants made more exploratory decisions (i.e., chose options without the highest expected reward value) and earned fewer points than controls in all three study days, and methylphenidate did not affect these outcomes. Baseline exploratory choices were positively associated with hyperactive ADHD symptoms across all participants. These results support several theoretical models of increased exploratory choices in ADHD and suggest the unexplained variance in ADHD decisions may be due to less value tracking. The inability to suppress actions with little to no reward value may be a key feature of hyperactive ADHD symptoms.

Effort-based decision making varies by smoking status.

RATIONALE: A reduced willingness to perform effort based on the magnitude and probability of potential rewards has been associated with diminished dopamine function and may be relevant to chronic drug use. OBJECTIVES: Here, we investigated the influence of smoking status on effort-based decisions. We hypothesized that smokers would make fewer high-effort selections than ex-smokers and never-smokers. METHODS: Current smokers (n = 25), ex-smokers (≥ 1 year quit, n = 23), and never-smokers (n = 19) completed the Effort Expenditure for Rewards Task in which participants select between low-effort and high-effort options to receive monetary rewards at varying levels of reward magnitude, probability and expected value. RESULTS: Overall, participants selected more high-effort options as potential reward magnitude and expected value increased. Smokers did not make fewer high-effort selections overall, but smokers were less sensitive to the changes in magnitude, probability, and expected value compared to never-smokers. Smokers were also less sensitive to the changes in probability and expected value, but not magnitude, compared to ex-smokers. Among smokers and ex-smokers, less nicotine dependence was associated with an increased likelihood of high-effort selections. CONCLUSIONS: These results demonstrate the relevance of smoking status to effort-based decisions and suggest that smokers have diminished sensitivity to nondrug reward value. Among ex-smokers, greater pre-existing sensitivity to reward value may have been conducive to smoking cessation, or sensitivity was improved by smoking cessation. Future prospective studies can investigate whether effort-related decision making is predictive of smoking initiation or cessation success. IMPLICATIONS: Willingness to perform effort to achieve a goal and sensitivity to changes in reward value are important aspects of motivation. These results showed that smokers have decreased sensitivity to changes in effort-related reward probability and expected value compared to ex-smokers and never-smokers. Potentially, improved sensitivity to rewards among ex-smokers may be a cause or consequence of smoking cessation. These findings may help explain why some smokers are able to achieve long-term abstinence.

The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate?

Caffeine is a commonly used neurostimulant that also produces cerebral vasoconstriction by antagonizing adenosine receptors. Chronic caffeine use results in an adaptation of the vascular adenosine receptor system presumably to compensate for the vasoconstrictive effects of caffeine. We investigated the effects of caffeine on cerebral blood flow (CBF) in increasing levels of chronic caffeine use. Low (mean = 45 mg/day), moderate (mean = 405 mg/day), and high (mean = 950 mg/day) caffeine users underwent quantitative perfusion magnetic resonance imaging on four separate occasions: twice in a caffeine abstinent state (abstained state) and twice in a caffeinated state following their normal caffeine use (native state). In each state, there were two drug conditions: participants received either caffeine (250 mg) or placebo. Gray matter CBF was tested with repeated-measures analysis of variance using caffeine use as a between-subjects factor, and correlational analyses were conducted between CBF and caffeine use. Caffeine reduced CBF by an average of 27% across both caffeine states. In the abstained placebo condition, moderate and high users had similarly greater CBF than low users; but in the native placebo condition, the high users had a trend towards less CBF than the low and moderate users. Our results suggest a limited ability of the cerebrovascular adenosine system to compensate for high amounts of daily caffeine use.

Low- and High-Frequency Repetitive Transcranial Magnetic Stimulation Effects on Resting-State Functional Connectivity Between the Postcentral Gyrus and the Insula.

The insular cortex supports the conscious awareness of physical and emotional sensations, and the ability to modulate the insula could have important clinical applications in psychiatry. Repetitive transcranial magnetic stimulation (rTMS) uses transient magnetic fields to induce electrical currents in the superficial cortex. Given its deep location in the brain, the insula may not be directly stimulated by rTMS; however, rTMS may modulate the insula via its functional connections with superficial cortical regions. Furthermore, low- versus high-frequency rTMS is thought to have opposing effects on cortical excitability, and the present study investigated these effects on brain activity and functional connectivity with the insula. Separate groups of healthy participants (n = 14 per group) received low (1 Hz)- or high (10 Hz)-frequency rTMS in five daily sessions to the right postcentral gyrus, a superficial region known to be functionally connected to the insula. Resting-state functional connectivity (RSFC) was measured pre- and post-rTMS. Both 1 and 10 Hz rTMS increased RSFC between the right postcentral gyrus and the left insula. These results suggest that low- and high-frequency rTMS has similar long-term effects on brain activity and RSFC. However, given the lack of difference, we cannot exclude the possibility that these effects are simply due to a nonspecific effect. Given this limitation, these unexpected results underscore the need for acoustic- and stimulation-matched sham control conditions in rTMS research.

Methylphenidate increases willingness to perform effort in adults with ADHD.

BACKGROUND: A reduced willingness to perform effort based on the magnitude and probability of potential rewards has been associated with diminished dopamine function and may be relevant to attention-deficit/hyperactivity disorder (ADHD). Here, we investigated the influence of ADHD status and methylphenidate on effort-based decisions. We hypothesized that ADHD participants would make fewer high-effort selections than non-ADHD subjects, and that methylphenidate would increase the number of high-effort selections. Furthermore, we hypothesized there would be associations among ADHD severity and methylphenidate-related changes in effort-based and attentional performance across all participants. METHODS AND PARTICIPANTS: ADHD (n = 23) and non-ADHD (n = 23) adults completed the Effort Expenditure for Rewards Task in which participants select between low-effort and high-effort options to receive monetary rewards at varying levels of reward magnitude and probability. A test of attentional performance was also completed. RESULTS: Overall, participants made more high-effort selections as potential reward magnitude and probability increased. ADHD participants did not make fewer high-effort selections than non-ADHD participants, but ADHD participants showed greater methylphenidate-related increases in high-effort selections. ADHD participants had worse attentional performance than non-ADHD participants. ADHD severity was associated with methylphenidate-related changes in high-effort selections, but not changes in attentional performance. CONCLUSIONS: These results indicate that methylphenidate increases the willingness to perform effort in individuals with ADHD, possibly due to disorder-related motivational deficits. This provides support for theories of insufficient effort allocation among individuals with ADHD. TRIAL REGISTRATION: Clinicaltrials.gov Identifier, NCT02630017.

Neural Mechanisms of Reward Prediction Error in Autism Spectrum Disorder.

Few studies have explored neural mechanisms of reward learning in ASD despite evidence of behavioral impairments of predictive abilities in ASD. To investigate the neural correlates of reward prediction errors in ASD, 16 adults with ASD and 14 typically developing controls performed a prediction error task during fMRI scanning. Results revealed greater activation in the ASD group in the left paracingulate gyrus during signed prediction errors and the left insula and right frontal pole during thresholded unsigned prediction errors. Findings support atypical neural processing of reward prediction errors in ASD in frontostriatal regions critical for prediction coding and reward learning. Results provide a neural basis for impairments in reward learning that may contribute to traits common in ASD (e.g., intolerance of unpredictability).

Comparison of 50- and 100-g L -tryptophan depletion and loading formulations for altering 5-HT synthesis: pharmacokinetics, side effects, and mood states.

RATIONALE: Differences in 5-hydroxytryptamine (5-HT) function have been the subject of extensive research in psychiatric studies. Many studies have manipulated L -tryptophan (Trp) levels to temporarily decrease (depletion) or increase (loading) 5-HT synthesis. While most researchers have used a 100-g formulation, there has been ongoing interest in using smaller-sized formulations. OBJECTIVES: This study examined the time course of multiple plasma indicators of brain 5-HT synthesis after a 50-g depletion and loading as a comparison to the corresponding 100-g formulations that are typically used. MATERIALS AND METHODS: Plasma was collected from 112 healthy adults at seven hourly intervals after consumption of either a 50- or 100-g depletion or loading. Self-ratings of mood and somatic symptoms were completed before and after Trp manipulations. RESULTS: The primary findings were that (1) the 50- and 100-g formulations produced the expected changes in plasma indicators after both depletion (-89% and -96%, respectively) and loading (+570% and +372%, respectively); (2) the 100-g depletion showed more robust effects at the 4, 5, and 6 h measurements than the 50-g depletion; (3) there was significant attrition after both the 100-g depletion and loading, but not after either of the 50-g formulations; and (4) both the 50- and 100-g depletions produced increases in negative self-ratings of mood and somatic symptoms, while loading significantly increased negative ratings after the 100 g only. CONCLUSIONS: There are important considerations when choosing among formulation sizes for use in Trp manipulation studies, and the complete 7-h time-course data set of the typical plasma Trp measures presented here may help researchers decide which methodology best suits their needs.

Distress tolerance to auditory feedback and functional connectivity with the auditory cortex.

Distress tolerance is the capacity to withstand negative affective states in pursuit of a goal. Low distress tolerance may bias an individual to avoid or escape experiences that induce affective distress, but the neural mechanisms underlying the bottom-up generation of distress and its relationship to behavioral avoidance are poorly understood. During a neuroimaging scan, healthy participants completed a mental arithmetic task with easy and distress phases, which differed in cognitive demands and positive versus negative auditory feedback. Then, participants were given the opportunity to continue playing the distress phase for a financial bonus and were allowed to quit at any time. The persistence duration was the measure of distress tolerance. The easy and distress phases activated auditory cortices and fronto-parietal regions. A task-based functional connectivity analysis using the left secondary auditory cortex (i.e., planum temporale) as the seed region revealed stronger connectivity to fronto-parietal regions and anterior insula during the distress phase. The distress-related connectivity between the seed region and the left anterior insula was negatively correlated with distress tolerance. The results provide initial evidence of the role of the anterior insula as a mediating link between the bottom-up generation of affective distress and top-down behavioral avoidance of distress.

ADHD, Smoking Withdrawal, and Inhibitory Control: Results of a Neuroimaging Study with Methylphenidate Challenge.

Smoking withdrawal negatively impacts inhibitory control, and these effects are greater for smokers with preexisting attention problems, such as attention deficit/hyperactivity disorder (ADHD). The current study preliminarily evaluated changes in inhibitory control-related behavior and brain activation during smoking withdrawal among smokers with ADHD. Moreover, we investigated the role of catecholamine transmission in these changes by examining the effects of 40 mg methylphenidate (MPH) administration. Adult daily smokers with (n=17) and without (n=20) ADHD completed fMRI scanning under each of three conditions: (a) smoking as usual+placebo; (b) 24 h smoking abstinence+placebo and (c) 24 h smoking abstinence+MPH. Scan order was randomized and counterbalanced. Participants completed a modified Go/No-Go task to assess both sustained and transient inhibitory control. Voxelwise analysis of task-related BOLD signal revealed a significant group-by-abstinence interaction in occipital/parietal cortex during sustained inhibition, with greater abstinence-induced decreases in activation observed among ADHD smokers compared with non-ADHD smokers. Changes in behavioral performance during abstinence were associated with changes in activation in regions of occipital and parietal cortex and bilateral insula during sustained inhibition in both groups. MPH administration improved behavioral performance and increased sustained inhibitory control-related activation for both groups. During transient inhibition, MPH increased prefrontal activation for both groups and increased striatal activation only among ADHD smokers. These preliminary findings suggest that abstinence-induced changes in catecholamine transmission in visual attention areas (eg, occipital and superior parietal cortex) may be associated with inhibitory control deficits and contribute to smoking vulnerability among individuals with ADHD.

Impulsive and premeditated subtypes of aggression in conduct disorder: differences in time estimation.

Research aimed at identifying and studying subtypes of aggression have historically dichotomized aggressive subtypes, although specific nomenclature has varied; one approach has been to classify aggressive behavior as predominantly impulsive or predominantly premeditated. There are a number of behavioral and cognitive differences between those exhibiting these different forms of aggression. This study was designed to extend understanding of the impulsive/premeditated aggression dichotomy by comparing time estimation among adolescents exhibiting predominantly impulsive or predominantly premeditated forms of physical aggression who have a psychiatric diagnosis of conduct disorder (CD). Time estimation has previously been shown to be disrupted in impulsive and some aggressive individuals. Time estimation was compared between healthy Controls (n = 37) and two groups of adolescents with CD, those with histories of either predominantly impulsive (CD-Impulsive, n = 26) or predominantly premeditated (CD-Premeditated, n = 38) aggressive behaviors. Participants completed five computerized trials during which they estimated when 1 min had passed. Among aggressive adolescents with CD, the misperception of time was specific to those with histories of impulsive aggression, although time estimates improved with repeated testing and performance feedback. This study confirms the importance of considering the role and type of physical aggression when studying heterogeneous diagnostic groups like CD and supports the relevance of time estimation to certain subgroups of adolescents with CD.