A Lifespan Model of Interference Resolution and Inhibitory Control: Risk for Depression and Changes with Illness Progression.

The cognitive processes involved in inhibitory control accuracy (IC) and interference resolution speed (IR) or broadly - inhibition - are discussed in this review, and both are described within the context of a lifespan model of mood disorders. Inhibitory control (IC) is a binary outcome (success or no for response selection and inhibition of unwanted responses) for any given event that is influenced to an extent by IR. IR refers to the process of inhibition, which can be manipulated by task design in earlier and later stages through use of distractors and timing, and manipulation of individual differences in response proclivity. We describe the development of these two processes across the lifespan, noting factors that influence this development (e.g., environment, adversity and stress) as well as inherent difficulties in assessing IC/IR prior to adulthood (e.g., cross-informant reports). We use mood disorders as an illustrative example of how this multidimensional construct can be informative to state, trait, vulnerability and neuroprogression of disease. We present aggregated data across numerous studies and methodologies to examine the lifelong development and degradation of this subconstruct of executive function, particularly in mood disorders. We highlight the challenges in identifying and measuring IC/IR in late life, including specificity to complex, comorbid disease processes. Finally, we discuss some potential avenues for treatment and accommodation of these difficulties across the lifespan, including newer treatments using cognitive remediation training and neuromodulation.

Neural correlates of inhibition and reward are negatively associated.

Individuals with impulsive and addictive disorders, including drug addiction, binge eating/obesity, and problem gambling, exhibit both impaired control over behavior and heightened sensitivity to reward. However, it is not known whether such deviation in inhibitory and reward circuitry among clinical populations is a cause or consequence of the disorders. Recent evidence suggests that these constructs may be related at the neural level, and together, increase risk for engaging in maladaptive behaviors. The current study examined the degree to which brain function during inhibition relates to brain function during receipt of reward in healthy young adults who have not yet developed problem behaviors. Participants completed the stop signal task to assess inhibitory control and the doors task to assess reactivity to monetary reward (win vs loss) during functional magnetic resonance imaging (fMRI). Brain activation during response inhibition was negatively correlated with brain activation during reward. Specifically, less brain activation in right prefrontal regions during inhibition, including the right inferior frontal gyrus, middle frontal gyrus, and supplementary motor area, was associated with greater brain activation in left ventral striatum during receipt of monetary reward. Moreover, these associations were stronger in binge drinkers compared to non-binge drinkers. These findings suggest that the systems are related even before the onset of impulsive or addictive disorders. As such, it is possible that the association between inhibitory and reward circuitry may be a prospective marker of risk.

Developmental changes in resting-state functional networks among individuals with and without internalizing psychopathologies.

BACKGROUND: Three well-established intrinsic connectivity networks (ICNs) involved in cognitive-affective processing include the cognitive control network (CCN), default mode network (DMN), and salience and emotional network (SEN). Despite recent advances in understanding developmental changes in these ICNs, the majority of research has focused on single seeds or networks in isolation with limited age ranges. Additionally, although internalizing psychopathologies (IPs), such as anxiety and depression, are often characterized by maladaptive cognitive-affective processing styles, it is not clear how IP history influences age-related changes in brain networks. METHOD: The current study aimed to characterize the normative development of the CCN, DMN, and SEN across a large age-span (7-29 year olds) of typically developing (TD) individuals (n = 97). We also explore how age may impact differences in network connectivity between TD individuals and patients with IPs (n = 136). RESULTS: Among TD individuals, DMN and CCN connectivity strengthened with age, whereas connectivity between the SEN and ventromedial prefrontal cortex weakened across development. When exploring group (IP vs. TD) differences, the IP group was characterized by greater connectivity between the CCN and cerebellum and between the SEN and caudate from childhood to early adulthood, relative to TD individuals. In addition, patients with IPs, versus TD individuals, exhibited reduced connectivity between the SEN and medial frontal gyrus from adolescence to adulthood. CONCLUSIONS: The current findings shed light on differential age-related changes in brain network patterns among psychiatrically free, TD individuals and those with internalizing disorders, and may provide plausible targets for novel mechanism-based treatments that differ based on developmental stage.

Multidimensional prediction of treatment response to antidepressants with cognitive control and functional MRI.

Predicting treatment response for major depressive disorder can provide a tremendous benefit for our overstretched health care system by reducing number of treatments and time to remission, thereby decreasing morbidity. The present study used neural and performance predictors during a cognitive control task to predict treatment response (% change in Hamilton Depression Rating Scale pre- to post-treatment). Forty-nine individuals diagnosed with major depressive disorder were enrolled with intent to treat in the open-label study; 36 completed treatment, had useable data, and were included in most data analyses. Participants included in the data analysis sample received treatment with escitalopram (n = 22) or duloxetine (n = 14) for 10 weeks. Functional MRI and performance during a Parametric Go/No-go test were used to predict per cent reduction in Hamilton Depression Rating Scale scores after treatment. Haemodynamic response function-based contrasts and task-related independent components analysis (subset of sample: n = 29) were predictors. Independent components analysis component beta weights and haemodynamic response function modelling activation during Commission errors in the rostral and dorsal anterior cingulate, mid-cingulate, dorsomedial prefrontal cortex, and lateral orbital frontal cortex predicted treatment response. In addition, more commission errors on the task predicted better treatment response. Together in a regression model, independent component analysis, haemodynamic response function-modelled, and performance measures predicted treatment response with 90% accuracy (compared to 74% accuracy with clinical features alone), with 84% accuracy in 5-fold, leave-one-out cross-validation. Convergence between performance markers and functional magnetic resonance imaging, including novel independent component analysis techniques, achieved high accuracy in prediction of treatment response for major depressive disorder. The strong link to a task paradigm provided by use of independent component analysis is a potential breakthrough that can inform ways in which prediction models can be integrated for use in clinical and experimental medicine studies.

Attenuated intrinsic connectivity within cognitive control network among individuals with remitted depression: Temporal stability and association with negative cognitive styles.

Many individuals with major depressive disorder (MDD) experience cognitive dysfunction including impaired cognitive control and negative cognitive styles. Functional connectivity magnetic resonance imaging studies of individuals with current MDD have documented altered resting-state connectivity within the default-mode network and across networks. However, no studies to date have evaluated the extent to which impaired connectivity within the cognitive control network (CCN) may be present in remitted MDD (rMDD), nor have studies examined the temporal stability of such attenuation over time. This represents a major gap in understanding stable, trait-like depression risk phenotypes. In this study, resting-state functional connectivity data were collected from 52 unmedicated young adults with rMDD and 47 demographically matched healthy controls, using three bilateral seeds in the CCN (dorsolateral prefrontal cortex, inferior parietal lobule, and dorsal anterior cingulate cortex). Mean connectivity within the entire CCN was attenuated among individuals with rMDD, was stable and reliable over time, and was most pronounced with the right dorsolateral prefrontal cortex and right inferior parietal lobule, results that were corroborated by supplemental independent component analysis. Attenuated connectivity in rMDD appeared to be specific to the CCN as opposed to representing attenuated within-network coherence in other networks (e.g., default-mode, salience). In addition, attenuated connectivity within the CCN mediated relationships between rMDD status and cognitive risk factors for depression, including ruminative brooding, pessimistic attributional style, and negative automatic thoughts. Given that these cognitive markers are known predictors of relapse, these results suggest that attenuated connectivity within the CCN could represent a biomarker for trait phenotypes of depression risk. Hum Brain Mapp 38:2939-2954, 2017. © 2017 Wiley Periodicals, Inc.

Preliminary Evidence for Disrupted Nucleus Accumbens Reactivity and Connectivity to Reward in Binge Drinkers.

AIMS: Dysfunctional brain reward circuitry, particularly in the nucleus accumbens (NAcc), has been proposed as a risk factor for alcohol use disorder (AUD). This risk factor may be evident in binge drinkers (BD), who are at high risk for developing AUD. We examined whole-brain and NAcc reactivity to reward in BD compared to non-binge drinkers (NBD), hypothesizing that groups would differ in their neural reactivity and connectivity. METHODS: Healthy BD (N = 27) and NBD (N = 23)-none meeting AUD criteria-completed a reward-guessing game, the 'Doors' task, during functional magnetic resonance imaging. We conducted an exploratory whole-brain search for group differences, but given our a priori hypotheses, we also extracted activation from the NAcc to examine reactivity during reward (Win > Loss) and functional connectivity (FC) to the prefrontal cortex. RESULTS: Compared to NBD, BD exhibited greater activation in both the right and left NAcc during reward relative to loss. Additionally, NBD drinkers exhibited positive FC between the NAcc and dorsal anterior cingulate (dACC) whereas the BD showed negative FC between these regions. Furthermore, less NAcc-dACC FC was related to more past month alcohol use. CONCLUSIONS: Our results provide preliminary evidence that BD exhibit greater NAcc activation during reward receipt relative to loss. This is consistent with the broader AUD literature and suggests aberrant neural reactivity may precede disorder onset. In addition, BD exhibited less NAcc-dACC FC, perhaps reflecting deficient regulation of activation to rewards compared to losses. This profile of reward brain circuitry could represent neural correlates of vulnerability for AUD. SHORT SUMMARY: Healthy binge drinkers, at risk for alcohol use disorder, exhibited greater nucleus accumbens activation during reward relative to loss. In addition, binge drinkers exhibited reduced connectivity between the nucleus accumbens and dorsal anterior cingulate, which was associated with more past month alcohol use.

Comorbid anxiety increases cognitive control activation in Major Depressive Disorder.

BACKGROUND: Major Depressive Disorder (MDD) and anxiety disorders often co-occur, with poorer treatment response and long-term outcomes. However, little is known about the shared and distinct neural mechanisms of comorbid MDD and anxiety (MDD+Anx). This study examined how MDD and MDD+Anx differentially impact cognitive control. METHODS: Eighteen MDD, 29 MDD+Anx, and 54 healthy controls (HC) completed the Parametric Go/No-Go (PGNG) during fMRI, including Target, Commission, and Rejection trials. RESULTS: MDD+Anx had more activation in the anterior dorsolateral prefrontal cortex, hippocampus, and caudate during Rejections, and inferior parietal lobule during correct Targets than MDD and HC. During Rejections HC had greater activation in a number of cognitive control regions compared to MDD; in the posterior cingulate compared to MDD+Anx; and in the fusiform gyrus compared to all MDD. During Commissions HC had greater activation in the right inferior frontal gyrus than all MDD. MDD had more activation in the mid-cingulate, inferior parietal lobule, and superior temporal gyrus than MDD+Anx during Commissions. CONCLUSIONS: Despite similar performance, MDD and MDD+Anx showed distinct differences in neural mechanisms of cognitive control in relation to each other, as well as some shared differences in relation to HC. The results were consistent with our hypothesis of hypervigilance in MDD+Anx within the cognitive control network, but inconsistent with our hypothesis that there would be greater engagement of salience and emotion network regions. Comorbidity of depression and anxiety may cause increased heterogeneity in study samples, requiring further specificity in detection and measurement of intermediate phenotypes and treatment Targets.

Dual-tasking gait variability and cognition in late-life depression.

OBJECTIVES: Studies have demonstrated an association between major depressive disorder (MDD) symptoms and fall risk in older adults, which may be at least partially mediated by executive functioning skills. There have also been observations of increased gait variability associated with fall risk and disease. This preliminary study first sought to understand whether gait variability in the context of dual task cost differs among older adults with MDD, relative to those with no history of psychiatric illness, and second, to identify relationships between gait variability measures and cognitive functioning in the context of MDD. METHODS: We recruited 15 older adults with MDD and 17 non-depressed (ND) community-dwelling older adults. All participants had impaired balance based on unipedal stance time. Assessments included neuropsychological measures and measures of gait variability using an instrumented gait mat (GAITRite© ) in the context of dual task relative to single task performance (i.e., dual task cost). RESULTS: The groups did not differ on any gait variability parameters. The MDD group demonstrated poorer performance in the psychomotor speed domain, relative to the ND group, but cognitive functioning between the groups in other domains was equivalent. In MDD, increased variability in stride time, stride velocity, and swing time during dual-tasking were associated with poorer executive functioning and visual memory. In ND, no significant relationships between gait variables and cognitive performance were observed. CONCLUSIONS: Findings suggest that unique cognitive mechanisms underlie mobility problems associated with fall risk in late-life depression.

Predicting Acute Changes in Suicidal Ideation and Planning: A Longitudinal Study of Symptom Mediators and the Role of the Menstrual Cycle in Female Psychiatric Outpatients With Suicidality.

OBJECTIVE: Cross-sectional and preliminary longitudinal findings suggest that cyclical ovarian hormone fluctuations influence acute suicide risk. The authors provide the first analyses in females with suicidality to investigate which daily symptoms covary with suicidal ideation and planning thoughts, the role of the menstrual cycle in daily symptom variation, how daily fluctuations in symptoms mediate the menstrual cycle-suicidality relationship, and how these associations vary across individuals. METHODS: Naturally cycling psychiatric outpatients (N=119) with past-month suicidal ideation provided daily ratings of psychiatric symptoms (depression, hopelessness, anxiety, feeling overwhelmed, agitation, anhedonia, worthlessness, rejection sensitivity, anger, perceived burdensomeness, and interpersonal conflict), suicidal ideation, and suicidal planning across at least one menstrual cycle. Symptom ratings were decomposed into trait (person-centered mean) and state (daily person-centered mean deviation) components. Five cycle phases were identified in relation to menses onset and ovulation (surge in urine luteinizing hormone level). Hypotheses were tested in multilevel structural equation models. RESULTS: Nearly all psychiatric symptoms covaried with fluctuations in daily suicidal ideation, and a limited set of symptoms (depression, hopelessness, rejection sensitivity, and perceived burdensomeness) predicted within-person increases in suicidal planning. Many patients demonstrated perimenstrual worsening of psychiatric symptoms, suicidal ideation, and suicidal planning. Depressive symptoms (depression, hopelessness, perceived burdensomeness, and anhedonia) were the most robust statistical mediators predicting perimenstrual exacerbation of suicidality. CONCLUSIONS: Research on the menstrual cycle and suicide has been limited historically by small, cross-sectional samples. This study provides the first evidence that measuring day-to-day correlates of suicidality in a large transdiagnostic sample of females with suicidal ideation can contribute to understanding the pathways by which the menstrual cycle influences acute suicide risk.

Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences.

Decades of research have examined the effects of cannabis on neurocognition. Recent advances in this field provide us with a better understanding of how cannabis use influences neurocognition both acutely (during intoxication) and non-acutely (after acute effects subside). Evidence of problems with episodic memory is one of the most consistent findings reported; however, several other neurocognitive domains appear to be adversely affected by cannabis use under various conditions. There is significant variability in findings across studies, thus a discussion of potential moderators is increasingly relevant. The purpose of this review was to 1) provide an update on research of cannabis' acute and non-acute effects on neurocognition, with a focus on findings since 2007 and 2) suggest and discuss how neurodevelopmental issues and sex differences may influence cannabis effects on neurocognition. Finally we discuss how future investigations may lead to better understanding of the complex interplay among cannabis, stages of neurodevelopment, and sex on neurocognitive functioning.

Preliminary evidence for a sex-specific relationship between amount of cannabis use and neurocognitive performance in young adult cannabis users.

Accumulating evidence suggests neuropsychological deficits from cannabis use, with a burgeoning area of preclinical research indicating possible sex-differences. However, few studies have examined how cannabis use may differentially impact neurocognition in male and female cannabis users. As such, we examined potential sex-differences in associations between amount of cannabis use (across several time frames) and neurocognitive performance among young adult regular cannabis users. Consistent with previous studies, more cannabis use was generally associated with poorer episodic memory and decision-making, but not other measures of inhibitory control. However, patterns of results suggested sex-specific dissociations. In particular, more cannabis use was more consistently associated with poorer episodic memory performance in females than males. Conversely, more cannabis use was associated with poorer decision-making performance for males, but not females. These results provide further evidence for residual cannabis-associated neurocognitive deficits and suggest the importance of examining the impact of cannabis on neurocognition separately for males and females.

Methamphetamine alters nucleus accumbens neural activation to monetary loss in healthy young adults.

RATIONALE: Stimulant drugs like methamphetamine (MA) activate brain reward circuitry, which is linked to the development of problematic drug use. It is not clear how drugs like MA alter neural response to a non-drug reward. OBJECTIVES: We examined how acute MA impacts neural response to receipt of a monetary reward relative to a loss in healthy adults. We hypothesized that MA (vs. placebo) would increase mesolimbic neural activation to reward, relative to loss. METHODS: In a within-subject, randomized, cross-over, double-blind, placebo-controlled design, 41 healthy adults completed the Doors monetary reward task during fMRI after ingestion of placebo or 20 mg MA. We examined drug effects on neural response to reward receipt (Win vs. Loss) using a priori anatomical striatal regions of interest (nucleus accumbens (NAcc), caudate, putamen). RESULTS: MA decreased NAcc BOLD activation to reward vs loss compared to placebo (p=.007) without altering caudate or putamen BOLD activation. Similar effects for reward vs. loss were obtained using whole brain analysis. Additional exploratory ROI analysis comparing reward and loss activation relative to a neutral "fixation" period indicated that MA increased NAcc BOLD activation during loss trials, without decreasing activation during win trials. CONCLUSIONS: This preliminary evidence suggests that MA increases NAcc neural response to the receipt of monetary loss. Additional studies are needed to replicate our findings and clarify the mechanisms contributing to altered mesolimbic neural response to reward and loss receipt during stimulant intoxication.

Preliminary evidence that individuals with remitted alcohol use disorder and major depressive disorder exhibit enhanced neural responses to reward: An EEG study.

INTRODUCTION: Disruptions in neural responses to reward are implicated in risk for Alcohol Use Disorder (AUD) and Major Depressive Disorder (MDD). It is not clear whether these findings extend to those in remission from AUD and MDD, a critical question as studies of remission can (a) rule out effects due to current symptoms, and (b) can reveal potential trait-like differences. METHODS: Individuals with and without remitted AUD (rAUD) and/or rMDD (rMDD) were drawn from a larger study to create four groups: rAUD (n = 54), rMDD (n = 66), rAUD + rMDD (n = 53), and a community control group (CCG; n = 81). Participants completed a validated monetary reward task during electroencephalogram (EEG). Multilevel models examined group differences in event-related potentials and time-frequency indices of reward and loss responsiveness, namely, reward positivity (RewP), feedback negativity (FN), reward-related delta power, and loss-related theta power. RESULTS: Analyses revealed that the rAUD + rMDD group had significantly higher reward-related delta activity than the three other groups (p-values < 0.01), which did not differ from each other. Sensitivity analyses revealed this relationship fell just above the threshold set for significance after controlling for residual current MDD and AUD symptoms (p =.05). There were no other group differences or significant interactions (p-values > 0.05). CONCLUSIONS: To our knowledge, this is the first study to show that individuals with remitted AUD and MDD demonstrate increased sensitivity to rewards compared to individuals with remitted AUD alone, MDD alone, and without AUD or MDD. These findings suggest heightened motivational salience to reward might be an important factor in comorbid AUD and MDD.

Effects of Cannabidiol in Adolescent and Young Adult Depressive and Anxiety Disorders: A Systematic Review of Clinical and Preclinical Research.

Background: Adolescents and young adults may use cannabidiol (CBD) products in an attempt to reduce depression and anxiety symptoms, despite little research examining this use. This systematic review evaluated preclinical and clinical research on the effects of CBD on depressive and anxiety disorders in adolescence and young adulthood. To provide context, we discuss CBD's mechanism of action and neurodevelopmental effects. Methods: PubMed was searched for articles published through June 2022. Preclinical or clinical CBD administration studies with N > 1 that examined depressive and/or anxiety disorders were eligible. Results: Initially, 224 publications were identified. After excluding duplicates and applying eligibility criteria, 6 preclinical (depression: n≈133; anxiety: n≈161) and 4 clinical (anxiety: n=113) articles remained. Due to the low number of studies, results were synthesized qualitatively. The Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence were used to rate each study's evidence. The preclinical effects of CBD on depression-like behavior appear to differ by sex, early life stress, and duration of use. Despite no evidence that CBD exerts anxiolytic effects in preclinical adolescent models, CBD may reduce anxiety symptoms in human adolescents and young adults with anxiety disorders. Conclusions: The existing evidence suggests that CBD may reduce symptoms of anxiety in adolescents and young adults. However, the evidence is sparse and limited by variations in samples and CBD dosing duration. Further research is needed to understand the potential benefits and/or harms of CBD for depression and anxiety disorders in this population. Implications for clinical practice and research are discussed.

Reduced connectivity of the cognitive control neural network at rest in young adults who had their first drink of alcohol prior to age 18.

The cognitive control network (CCN) is an important network responsible for performing and modulating executive functions. In adolescents, alcohol use has been associated with weaker cognitive control, higher reward sensitivity, and later-in-life alcohol problems. Given that the CCN continues to develop into young adulthood, it is important to understand relations between early alcohol use, the CCN, and reward networks. Participants included individuals 18-23 years without alcohol use disorder. Based upon self-reported age of first alcoholic drink, participants were split into two groups: Early (onset) Drinkers (first drink < age 18, N = 52) and Late (onset) Drinkers (first drink > age 18, N = 44). All participants underwent an 8-minute resting-state fMRI scan. Seed regions of interest included the anterior dorsolateral prefrontal cortex (DLPFC), amygdala, and ventral striatum. Early Drinkers demonstrated significant reduced connectivity of CCN regions, including bilateral anterior DLPFC, compared to Late Drinkers. There were no significant differences between Early and Late Drinkers in connectivity between reward and CCN regions. These results suggest that individuals who begin drinking alcohol earlier in life may have alterations in the development of the CCN; however, longitudinal research is necessary to determine whether lower connectivity precedes or follows early alcohol use, and any other relevant factors.

The influence of inhibitory control and episodic memory on the risky sexual behavior of young adult cannabis users.

Cannabis use is associated with risky sexual behavior (RSB) and sex-related negative health consequences. This investigation examined the role of inhibitory control and episodic memory in predicting RSB and sex-related negative consequences among current cannabis users. Findings indicated that the relationships among cannabis, neurocognition, and sexual-risk varied according to the dimension of neurocognition and the parameter of RSB in question. Specifically, more risk-taking was associated with more RSB. Furthermore, amount of recent cannabis use was associated with more RSB and sex-related negative consequences, but only among those with worse performances on a measure of decision-making and of risk-taking. Contrary to hypotheses, worse episodic memory also significantly predicted higher overall sexual-risk and decreased safe-sex practices. Results indicate that worse neurocognitive performance in the areas of risk-taking, decision-making, and episodic memory may influence the degree to which cannabis users engage in RSB and experience negative health consequences as a result. (JINS, 2012, 18, 1-7).

Electrocortical measures of win and loss processing are associated with mesocorticolimbic functional connectivity: A combined ERP and rs-fMRI study.

The reward positivity (RewP) event-related potential is a well-validated measure of reward processing implicated in internalizing psychopathologies. The RewP is thought to reflect reward reactivity in the mesocorticolimbic system; however, it is not clear how the RewP is related to the functional connectivity of reward-related brain regions. The current study examined associations between the RewP (Win and Loss residuals) and resting-state fMRI (rs-fMRI), among adults with internalizing psychopathology (IP) and healthy controls (HC). All participants (N = 102) completed a validated monetary reward task during electroencephalogram and rs-fMRI. Regression analyses were conducted with (1) RewP-Win residual amplitude and striatal seeds (caudate, putamen, nucleus accumbens) and (2) RewP-Loss residual amplitude and anterior cingulate cortex (ACC) seeds. Overall, individuals with greater RewP-Win residual amplitude demonstrated increased rs-fMRI connectivity between striatal regions and the medial prefrontal cortex, as well as the parahippocampal gyrus, but decreased connectivity between striatal regions and regions involved in cognitive control and sensorimotor processing. Greater RewP-Loss residual was related to greater connectivity between the ACC and regions involved in reward/loss processing and motor control, but decreased connectivity between the ACC and regions involved in cognitive control. Relationships between the RewP and rs-fMRI were generally consistent across IP and HC. However, a few patterns were unique to IP. Results indicate the RewP is associated with resting-state functional connectivity of reward- and loss-related brain regions, suggesting connectivity of the mesocorticolimbic system may be an important individual difference factor in dimensions of attainment of reward and loss.

Effect of Δ9-Tetrahydrocannabinol on frontostriatal resting state functional connectivity and subjective euphoric response in healthy young adults.

BACKGROUND: Few studies have examined how Δ9-Tetrahydrocannabinol (THC), the main psychoactive component of cannabis, impacts brain reward circuitry in humans. In this study, we examined if an acute dose of THC altered resting state functional connectivity between the striatum and prefrontal cortex among healthy young adults with limited cannabis use. METHODS: Participants received THC (n = 24) or placebo (n = 22) in a double-blind, randomized, between-subject design. Participants completed self-report measures of euphoria and drug-liking throughout the visit. Approximately 120 min after drug administration, participants completed an 8-min resting state functional MRI (rs-fMRI) scan. We utilized seed-based connectivity of the striatum (bilateral putamen, caudate, and NAcc seeds) to the frontal cortex. RESULTS: Individuals who received THC demonstrated greater rs-fMRI connectivity between the right NAcc and regions of the medial prefrontal cortex (mPFC) (p-values<0.05, corrected) and higher subjective euphoria ratings (p = .03) compared to compared to individuals who received placebo. Higher ratings of euphoria were related to greater right NAcc-dorsal mPFC (dmPFC) connectivity for the THC group (p=.03), but not for the placebo group (p=.98). CONCLUSIONS: This is one of the first studies to examine rs-fMRI connectivity in healthy young non-users after THC administration. We found individuals receiving THC show greater rs-fMRI connectivity between the NAcc and mPFC, regions implicated in reward, compared to individuals receiving placebo. In addition, individuals receiving THC reported higher subjective euphoria ratings, which were positively associated with NAcc-dmPFC connectivity. Overall, our findings suggest THC may produce subjective and neural reward responses that contribute to the rewarding, reinforcing properties of cannabis.

Risk factors for alcohol, marijuana, and cigarette polysubstance use during adolescence and young adulthood: A 7-year longitudinal study of youth at high risk for smoking escalation.

INTRODUCTION: Alcohol, nicotine, and marijuana are the three most widely used substances among adolescents and young adults, with co-use of multiple substances being common. Few longitudinal studies have examined risk factors of alcohol, marijuana, and nicotine poly-substance use. We examined frequency of alcohol, marijuana, and cigarette poly-substance use over time and how key risk factors contribute to this substance use during adolescence and young adulthood. METHODS: Participants (N = 1263 9th and 10th graders) were oversampled for ever-smoking a cigarette at baseline from 16 Chicago-area high schools between 2004 and 2006. Many participants progressed to heavier cigarette use, as well as alcohol and marijuana use over time. Participants completed questionnaires assessing substance use and psychosocial factors at baseline, 6-, 15-, 24-, 33-months, and 5-, 6-, and 7-years. RESULTS: Longitudinal multi-level models demonstrated that at baseline and over time, more depression symptoms, more anxiety symptoms, negative mood regulation expectancies, and lower grade point average (GPA) were each associated with more poly-substance use over time. In addition, there were a number of interaction effects of gender (e.g., depression was related to substance use in males) and developmental stage moderated these relationships. CONCLUSIONS: Depression, anxiety, negative mood regulation expectancies, and GPA all significantly influence both initial and longitudinal levels of substance use across adolescence and young adulthood. Our findings underscore the importance of identifying and treating youth with depression and anxiety symptoms, as well as providing resources early for those struggling in school in order to help with substance use prevention and intervention efforts.

Individual differences in striatal and amygdala response to emotional faces are related to symptom severity in social anxiety disorder.

Social anxiety disorder (SAD) is a common heterogeneous disorder characterized by excessive fear and deficient positive experiences. Case-control emotion processing studies indicate that altered amygdala and striatum function may underlie SAD; however, links between these regions and symptomatology have yet to be established. Therefore, in the current study, 80 individuals diagnosed with SAD completed a validated emotion processing task during functional magnetic resonance imaging. Anatomy-based regions of interest were amygdala, caudate, putamen, and nucleus accumbens. Neural activity in response to angry > happy faces and fearful > happy faces in these regions were submitted to multiple linear regression analysis with bootstrapping. Additionally, multiple linear regression analysis was performed to explore clinical features of SAD. Results showed greater putamen activity and less amygdala activity in response to angry > happy faces were related to greater social anxiety severity. In the model consisting of caudate and amygdala activity in response to angry > happy faces, results were marginally related to social anxiety severity and the pattern of activity was similar to the regression model comprising putamen and amygdala. Nucleus accumbens activity was not related to social anxiety severity. There was no correspondence between brain activity in response to fearful > happy faces and social anxiety severity. Clinical variables revealed greater levels of anhedonia and general anxiety were related to social anxiety severity, however, neural activity was not related to these features of SAD. Neuroimaging findings suggest that variance in dorsal striatal and amygdala activity in response to certain social signals of threat contrasted with an approach/rewarding social signal may contribute to individual differences in SAD. Clinical findings indicate variance in anhedonia and general anxiety symptoms may contribute to individual differences in social anxiety severity.