Compulsive drug-taking is associated with habenula-frontal cortex connectivity.

As a critical node connecting the forebrain with the midbrain, the lateral habenula (LHb) processes negative feedback in response to aversive events and plays an essential role in value-based decision-making. Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal-midbrain circuits. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a "compulsivity index (CI)," defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal-LHb-SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.

Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment-resistant individuals.

Substance use disorders (SUDs) impose severe negative impacts upon individuals, their families, and society. Clinical studies demonstrate that some chronic stimulant users are able to curtail their drug use when faced with adverse consequences while others continue to compulsively use drugs. The mechanisms underlying this dichotomy are poorly understood, which hampers the development of effective individualized treatments of a disorder that currently has no Food and Drug Administration-approved pharmacological treatments. In the present study, using a rat model of methamphetamine self-administration (SA) in the presence of concomitant foot shocks, thought to parallel compulsive drug taking by humans, we found that SA behavior correlated with alterations in the balance between an increased orbitofrontal cortex-dorsomedial striatal "go" circuit and a decreased prelimbic cortex-ventrolateral striatal "stop" circuit. Critically, this correlation was seen only in rats who continued to self-administer at a relatively high rate despite receiving foot shocks of increasing intensity. While the stop circuit functional connectivity became negative after repeated SA in all rats, "shock-resistant" rats showed strengthening of this negative connectivity after shock exposure. In contrast, "shock-sensitive" rats showed a return toward their baseline levels after shock exposure. These results may help guide novel noninvasive brain stimulation therapies aimed at restoring the physiological balance between stop and go circuits in SUDs.

Repetitive Transcranial Magnetic Stimulation Delivered With an H-Coil to the Right Insula Reduces Functional Connectivity Between Insula and Medial Prefrontal Cortex.

OBJECTIVE: Insula neurocircuitry alterations are reported in a range of neuropsychiatric disorders holding promise for clinical interventions. We measured, in a pilot study, acute neuroplastic modulations resulting from high- and low-frequency stimulation with repetitive transcranial magnetic stimulation (rTMS) delivered via an H-coil that targeted the right insula and overlying prefrontal cortex. METHODS: Healthy, nonsmoking, adult participants (N = 28), in a within-participant, sham-controlled experiment, received a single rTMS session on four separate days. Participants received one session each of low- (1 Hz) and high (10 Hz)-frequency stimulation and two sessions of sham stimulation matched to each rTMS frequency. After each rTMS session, participants completed a functional magnetic resonance imaging (fMRI) scan while performing two cognitive tasks and a resting-state scan. The effect of rTMS was examined on task behavior as well as blood oxygenated level-dependent (BOLD) response during task performance and resting state. We expected low- and high-frequency stimulation to decrease and increase, respectively, insula and overlying cortical BOLD signal and network connectivity. RESULTS/CONCLUSIONS: There was no effect of rTMS, regardless of frequency, on task behavior or task-based BOLD response. There was an effect of rTMS compared to sham on rsFC between insula and medial prefrontal cortex, with connectivity reduced after rTMS compared to sham, regardless of frequency. Implications for using rTMS to the insula as a treatment for neuropsychiatric disorders are discussed in light of insula-medial prefrontal cortex connectivity.

Evidence of subgroups in smokers as revealed in clinical measures and evaluated by neuroimaging data: a preliminary study.

To date, fractionation of the nicotine addiction phenotype has been limited to that based primarily on characteristics of cigarette use, although it is widely appreciated that a variety of individual factors are associated with tobacco use disorder. Identifying subtypes of tobacco use disorder based on such factors may lead to better understanding of potential treatment targets, individualize treatments and improve outcomes. In this preliminary study, to identify potential subgroups, we applied hierarchical clustering to a broad range of assessments measuring personality, IQ and psychiatric symptoms, as well as various environmental and experiential characteristics from 102 otherwise healthy cigarette smokers. The identified subgroups were further compared on various resting-state fMRI measures from a subset (N = 65) of individuals who also underwent resting-state fMRI scanning. The clustering dendrogram indicated that smokers can be divided into three subgroups. Each subgroup had unique clinical assessment characteristics. The division yielded imaging differences between subgroups in the supplementary motor area/middle cingulate cortex and the cuneus. Regression analyses showed that amplitude of low frequency fluctuations in the supplementary motor area/middle cingulate cortex differed between groups and were negatively correlated with the Toronto Alexithymia Scale subscale Difficulty Describing Feelings.

Salience and default mode network dysregulation in chronic cocaine users predict treatment outcome.

While chronic cocaine use is associated with abnormalities in both brain structure and function within and interactions between regions, previous studies have been limited to interrogating structure and function independently, and the detected neural differences have not been applied to independent samples to assess the clinical relevance of results. We investigated consequences of structural differences on resting-state functional connectivity in cocaine addiction and tested whether resting-state functional connectivity of the identified circuits predict relapse in an independent cohort. Subjects included 64 non-treatment-seeking cocaine users (NTSCUs) and 67 healthy control subjects and an independent treatment-completed cohort (n = 45) of cocaine-dependent individuals scanned at the end of a 30-day residential treatment programme. Differences in cortical thickness and related resting-state functional connectivity between NTSCUs and healthy control subjects were identified. Survival analysis, applying cortical thickness of the identified regions, resting-state functional connectivity of the identified circuits and clinical characteristics to the treatment cohort, was used to predict relapse. Lower cortical thickness in bilateral insula and higher thickness in bilateral temporal pole were found in NTSCUs versus healthy control subjects. Whole brain resting-state functional connectivity analyses with these four different anatomical regions as seeds revealed eight weaker circuits including within the salience network (insula seeds) and between temporal pole and elements of the default mode network in NTSCUs. Applying these circuits and clinical characteristics to the independent cocaine-dependent treatment cohort, functional connectivity between right temporal pole and medial prefrontal cortex, combined with years of education, predicted relapse status at 150 days with 88% accuracy. Deficits in the salience network suggest an impaired ability to process physiologically salient events, while abnormalities in a temporal pole-medial prefrontal cortex circuit might speak to the social-emotional functional alterations in cocaine addiction. The involvement of the temporal pole-medial prefrontal cortex circuit in a model highly predictive of relapse highlights the importance of social-emotional functions in cocaine dependence, and provides a potential underlying neural target for therapeutic interventions, and for identifying those at high risk of relapse.

Interactions between the salience and default-mode networks are disrupted in cocaine addiction.

Cocaine dependence is a complex neuropsychiatric disorder manifested as dysregulation of multiple behavioral, emotional, and cognitive constructs. Neuroimaging studies have begun to identify specific neurobiological circuit impairments in cocaine-dependent (CD) individuals that may underlie these symptoms. However, whether, where, and how the interactions within and between these circuits are disrupted remain largely unknown. We used resting-state fMRI and modularity network analysis to identify brain modules of a priori interest (default-mode network [DMN], salience network [SN], executive control network [ECN], medial temporal lobe [MTL], and striatum) in 47 CD and 47 matched healthy control (HC) participants and explored alterations within and between these brain modules as a function of addiction. At the module level, intermodule connectivity decreased between DMN and SN in CD. At the nodal level, several regions showed decreased connections with multiple modules in CD: the rostral anterior cingulate connection strength was reduced with SN and MTL; the posterior cingulate had reduced connections with ECN; and the bilateral insula demonstrated decreased connections with DMN. Furthermore, alexithymia, a personality trait previously associated with addiction, correlated negatively with intramodule connectivity within SN only in cocaine users. Our results indicate that cocaine addiction is associated with disrupted interactions among DMN, MTL, and SN, which have been implicated, respectively, in self-referential functions, emotion and memory, and coordinating between internal and external stimuli, providing novel and important insights into the neurobiological mechanisms of cocaine addiction.

Greater externalizing personality traits predict less error-related insula and anterior cingulate cortex activity in acutely abstinent cigarette smokers.

Attenuated activity in performance-monitoring brain regions following erroneous actions may contribute to the repetition of maladaptive behaviors such as continued drug use. Externalizing is a broad personality construct characterized by deficient impulse control, vulnerability to addiction and reduced neurobiological indices of error processing. The insula and dorsal anterior cingulate cortex (dACC) are regions critically linked with error processing as well as the perpetuation of cigarette smoking. As such, we examined the interrelations between externalizing tendencies, erroneous task performance, and error-related insula and dACC activity in overnight-deprived smokers (n = 24) and non-smokers (n = 20). Participants completed a self-report measure assessing externalizing tendencies (Externalizing Spectrum Inventory) and a speeded Flanker task during functional magnetic resonance imaging scanning. We observed that higher externalizing tendencies correlated with the occurrence of more performance errors among smokers but not non-smokers. Suggesting a neurobiological contribution to such suboptimal performance among smokers, higher externalizing also predicted less recruitment of the right insula and dACC following error commission. Critically, this error-related activity fully mediated the relationship between externalizing traits and error rates. That is, higher externalizing scores predicted less error-related right insula and dACC activity and, in turn, less error-related activity predicted more errors. Relating such regional activity with a clinically relevant construct, less error-related right insula and dACC responses correlated with higher tobacco craving during abstinence. Given that inadequate error-related neuronal responses may contribute to continued drug use despite negative consequences, these results suggest that externalizing tendencies and/or compromised error processing among subsets of smokers may be relevant factors for smoking cessation success.

Relations among prospective memory, cognitive abilities, and brain structure in adolescents who vary in prenatal drug exposure.

This investigation examined how prospective memory (PM) relates to cognitive abilities (i.e., executive function, attention, working memory, and retrospective memory) and brain structure in adolescents who vary in prenatal drug exposure (PDE). The sample consisted of 105 (55 female and 50 male) urban, primarily African American adolescents (mean age=15.5 years) from low socioeconomic status (SES) families. Approximately 56% (n=59) were prenatally exposed to drugs (heroin and/or cocaine) and 44% (n=46) were not prenatally exposed, but the adolescents were similar in age, gender, race, and SES. Executive functioning, attentional control, working memory, retrospective memory, and overall cognitive ability were assessed by validated performance measures. Executive functioning was also measured by caregiver report. A subset of 52 adolescents completed MRI (magnetic resonance imaging) scans, which provided measures of subcortical gray matter volumes and thickness of prefrontal, parietal, and temporal cortices. Results revealed no differences in PM performance by PDE status, even after adjusting for age and IQ. Executive function, retrospective memory, cortical thickness in frontal and parietal regions, and volume of subcortical regions (i.e., putamen and hippocampus) were related to PM performance in the sample overall, even after adjusting for age, IQ, and total gray matter volume. Findings suggest that variations in PM ability during adolescence are robustly related to individual differences in cognitive abilities, in particular executive function and retrospective memory, and brain structure, but do not vary by PDE status.

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.

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.

Individual differences in amygdala reactivity following nicotinic receptor stimulation in abstinent smokers.

Hyperactive amygdala functioning may underlie emotional dysregulation during smoking abstinence and represents one neurobiological target for pharmacological cessation aids. Available pharmacotherapies (e.g., nicotine replacement and varenicline) aid only a subset of individuals with smoking cessation and therefore elucidating the neurobiological impact of these medications is critical to expedite improved interventions. In a fMRI study employing a within-subject, double-blind, placebo-controlled design, we assessed task performance and amygdala functioning during an emotional face matching paradigm following administration of nicotine and varenicline to 24 abstinent smokers and 20 nonsmokers. All participants underwent ~17days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. During the amygdala reactivity paradigm, nicotinic acetylcholine receptor (nAChR) stimulation by nicotine and varenicline decreased reaction time (RT) in abstinent smokers but not in nonsmokers. When considering all smokers as a single homogenous group, no drug-induced effects on amygdala reactivity were detected. However, in an exploratory analysis we parsed participants into subgroups according to individual differences in the propensity to demonstrate stable performance augmentation following nAChR stimulation (stable RT-improvers [SI] vs. variable RT-improvers [VI]). Using this exploratory approach, drugs appeared to modulate amygdala reactivity in only one smoker subgroup but not in either nonsmoker subgroup. Specifically, in the SI-smoker cohort abstinence-induced elevated amygdala reactivity was down-regulated by nAChR stimulation. In contrast, varenicline and nicotine did not modulate amygdala functioning in the VI-smoker cohort who displayed moderate levels of amygdala reactivity in the absence of drug administration. These results suggest that pharmacotherapies most robustly dampened amygdala functioning in smokers appearing susceptible to abstinence-induced effects. Such findings provide a step towards fractionating the smoker phenotype by discrete neurobiological characteristics.

Prefrontal white matter impairment in substance users depends upon the catechol-o-methyl transferase (COMT) val158met polymorphism.

Individuals addicted to most chemical substances present with hypoactive dopaminergic systems as well as altered prefrontal white matter structure. Prefrontal dopaminergic tone is under genetic control and is influenced by and modulates descending cortico-striatal glutamatergic pathways that in turn, regulate striatal dopamine release. The catechol-O-methyltransferase (COMT) gene contains an evolutionarily recent and common functional variant at codon 108/158 (rs4680) that plays an important role in modulating prefrontal dopaminergic tone. To determine if the COMT val158met genotype influences white matter integrity (i.e., fractional anisotropy (FA)) in substance users, 126 healthy controls and 146 substance users underwent genotyping and magnetic resonance imaging. A general linear model with two between-subjects factors (COMT genotype and addiction status) was performed using whole brain diffusion tensor imaging (DTI) to assess FA. A significant Genotype × Drug Use status interaction was found in the left prefrontal cortex. Post-hoc analysis showed reduced prefrontal FA only in Met/Met homozygotes who were also drug users. These data suggest that Met/Met homozygous individuals, in the context of addiction, have increased susceptibility to white matter structural alterations, which might contribute to previously identified structural and functional prefrontal cortical deficits in addiction.

A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction.

Whole-genome searches have identified nicotinic acetylcholine receptor alpha5-alpha3-beta4 subunit gene variants that are associated with smoking. How genes support this addictive and high-risk behavior through their expression in the brain remains poorly understood. Here we show that a key alpha5 gene variant Asp398Asn is associated with a dorsal anterior cingulate-ventral striatum/extended amygdala circuit, such that the "risk allele" decreases the intrinsic resting functional connectivity strength in this circuit. Importantly, this effect is observed independently in nonsmokers and smokers, although the circuit strength distinguishes smokers from nonsmokers, predicts addiction severity in smokers, and is not secondary to smoking per se, thus representing a trait-like circuitry biomarker. This same circuit is further impaired in people with mental illnesses, who have the highest rate of smoking. Identifying where and how brain circuits link genes to smoking provides practical neural circuitry targets for new treatment development.

Disrupted Dynamic Interactions Between Large-Scale Brain Networks in Cocaine Users Are Associated With Dependence Severity.

BACKGROUND: Substance use disorder is conceptualized as a neuropsychiatric disease with multifaceted phenotypic manifestations including disrupted interactions between brain networks. While the current understanding of brain network interactions is mostly based on static functional connectivity, accumulating evidence suggests that temporal dynamics of these network interactions may better reflect brain function and disease-related dysfunction. We thus investigated brain dynamics in cocaine use disorder and assessed their relationship with cocaine dependence severity. METHODS: Using a time frame analytical approach on resting-state functional magnetic resonance imaging data of 54 cocaine users and 54 age- and sex-matched healthy control participants, we identified temporally recurring brain network configuration patterns, termed brain states. With Menon's triple network model as a guide, we characterized these state dynamics by quantifying their occurrence rate and transition probability. Group differences in the state dynamics and their association with cocaine dependence were assessed. RESULTS: Three recurrent brain states with spatial patterns resembling the default mode, salience, and executive control networks were identified. Compared with healthy control subjects, cocaine users showed a higher default mode state occurrence rate and higher probability of transitioning from the salience state to the default mode state, with the former being attributed to the latter. A composite state transition probability negatively correlated with cocaine dependence severity. CONCLUSIONS: Our results provide novel evidence supporting the triple network model. While confirming hyperactivity of default mode network in cocaine users, our findings indicate the failure of salience network in toggling between default mode and executive control networks in cocaine use disorder.

Brain Functional Connectome Defines a Transdiagnostic Dimension Shared by Cognitive Function and Psychopathology in Preadolescents.

BACKGROUND: Cognitive function and general psychopathology are two important classes of human behavior dimensions that are individually related to mental disorders across diagnostic categories. However, whether these two transdiagnostic dimensions are linked to common or distinct brain networks that convey resilience or risk for the development of psychiatric disorders remains unclear. METHODS: The current study is a longitudinal investigation with 11,875 youths from the Adolescent Brain Cognitive Development (ABCD) Study at ages 9 to 10 years at the onset of the study. A machine learning approach based on canonical correlation analysis was used to identify latent dimensional associations of the resting-state functional connectome with multidomain behavioral assessments including cognitive functions and psychopathological measures. For the latent resting-state functional connectivity factor showing a robust behavioral association, its ability to predict psychiatric disorders was assessed using 2-year follow-up data, and its genetic association was evaluated using twin data from the same cohort. RESULTS: A latent functional connectome pattern was identified that showed a strong and generalizable association with the multidomain behavioral assessments (5-fold cross-validation: ρ = 0.68-0.73 for the training set [n = 5096]; ρ = 0.56-0.58 for the test set [n = 1476]). This functional connectome pattern was highly heritable (h2 = 74.42%, 95% CI: 56.76%-85.42%), exhibited a dose-response relationship with the cumulative number of psychiatric disorders assessed concurrently and at 2 years post-magnetic resonance imaging scan, and predicted the transition of diagnosis across disorders over the 2-year follow-up period. CONCLUSIONS: These findings provide preliminary evidence for a transdiagnostic connectome-based measure that underlies individual differences in the development of psychiatric disorders during early adolescence.

Not all smokers are alike: the hidden cost of sustained attention during nicotine abstinence.

Nicotine Withdrawal Syndrome (NWS)-associated cognitive deficits are notably heterogeneous, suggesting underlying endophenotypic variance. However, parsing this variance in smokers has remained challenging. In this study, we identified smoker subgroups based on response accuracy during a Parametric Flanker Task (PFT) and then characterized distinct neuroimaging endophenotypes using a nicotine state manipulation. Smokers completed the PFT in two fMRI sessions (nicotine sated, abstinent). Based on response accuracy in the stressful, high cognitive demand PFT condition, smokers split into high (HTP, n = 21) and low task performer (LTP, n = 24) subgroups. Behaviorally, HTPs showed greater response accuracy (88.68% ± 5.19 SD) vs. LTPs (51.04% ± 4.72 SD), independent of nicotine state, and greater vulnerability to abstinence-induced errors of omission (EOm, p = 0.01). Neurobiologically, HTPs showed greater BOLD responses in attentional control brain regions, including bilateral insula, dorsal ACC, and frontoparietal Cx for the [correct responses (-) errors of commission] PFT contrast in both states. A whole-brain functional connectivity (FC) analysis with these subgroup-derived regions as seeds identified two circuits: Precentral Cx↔Insula and Insula↔Occipital Cx, with abstinence-induced FC strength increases seen only in HTPs. Finally, abstinence-induced FC and behavior (EOm) differences were positively correlated for HTPs in a Precentral Cx↔Orbitofrontal cortical circuit. In sum, only the HTP subgroup demonstrated sustained attention deficits following 48-hr nicotine abstinence, a stressor in dependent smokers. Unpacking underlying smoker heterogeneity with this 'dual (task and abstinence) stressor' approach revealed discrete smoker subgroups with differential attentional deficits to withdrawal that could be novel pharmacological/behavioral targets for therapeutic interventions to improve cessation outcomes.

Factors underlying prefrontal and insula structural alterations in smokers.

Based upon previous reports of alterations in white matter integrity and gray matter density in smokers, we examined these markers in a large, well-matched sample of smokers and non-smokers. We further investigated the effect of heavy cigarette exposure by using pack-years and the effects of two relatively stable, highly heritable traits in smokers (Fagerström Test of Nicotine Dependence (FTND), a measure of severity of nicotine dependence and Toronto Alexithymia Scale (TAS-20), a stable personality trait related to smoking). Forty-eight nicotine-dependent subjects and 48 matched controls were included in the analyses, with smokers also subdivided into high/low dependence and high/low pack-years smokers. White matter integrity (fractional anisotropy (FA)) and gray matter density (voxel-based morphometry (VBM)) were measured and compared across groups. Gray matter density was lower in left prefrontal cortex (PFC) in high pack-years smokers and was inversely related to pack-years. In contrast, left insular cortex gray matter density was higher in smokers and associated with TAS-20 total score and with difficulty-identifying-feelings factor. Further, the most highly dependent smokers showed lower prefrontal FA, which was negatively correlated with FTND. There was no correlation between pack-years and FTND in our smoker population. These data suggest chronic tobacco use is correlated with prefrontal gray matter damage , while differences in insula gray matter and PFC white matter appear to reflect stable and heritable differences between smokers and non-smokers.

Anatomical differences and network characteristics underlying smoking cue reactivity.

A distributed network of brain regions is linked to drug-related cue responding. However, the relationships between smoking cue-induced phasic activity and possible underlying differences in brain structure, tonic neuronal activity and connectivity between these brain areas are as yet unclear. Twenty-two smokers and 22 controls viewed smoking-related and neutral pictures during a functional arterial spin labeling scanning session. T1, resting functional, and diffusion tensor imaging data were also collected. Six brain areas, dorsal lateral prefrontal cortex (dlPFC), dorsal medial prefrontal cortex (dmPFC), dorsal anterior cingulate cortex/cingulate cortex, rostral anterior cingulate cortex (rACC), occipital cortex, and insula/operculum, showed significant smoking cue-elicited activity in smokers when compared with controls and were subjected to secondary analysis for resting state functional connectivity (rsFC), structural, and tonic neuronal activity. rsFC strength between rACC and dlPFC was positively correlated with the cue-elicited activity in dlPFC. Similarly, rsFC strength between dlPFC and dmPFC was positively correlated with the cue-elicited activity in dmPFC while rsFC strength between dmPFC and insula/operculum was negatively correlated with the cue-elicited activity in both dmPFC and insula/operculum, suggesting these brain circuits may facilitate the response to the salient smoking cues. Further, the gray matter density in dlPFC was decreased in smokers and correlated with cue-elicited activity in the same brain area, suggesting a neurobiological mechanism for the impaired cognitive control associated with drug use. Taken together, these results begin to address the underlying neurobiology of smoking cue salience, and may speak to novel treatment strategies and targets for therapeutic interventions.

Single subject task-related BOLD signal artifact in a real-time fMRI feedback paradigm.

Real-time functional magnetic resonance imaging (rtfMRI) has been proposed as a method of providing feedback to develop a participant's ability to control his or her own neuronal activity. However, this BOLD signal is vulnerable to contamination from nonneuronal sources that can also be shaped by the feedback provided. Here we illustrate an artifact found while training participants to control signal from an ROI in the insula. As the artifact was directly behind the eye and the experiment used an echo-planar imaging (EPI) sequence with phase encoding direction that included the orbits and the insula in the same line, we hypothesized that the artifact was due to eye motion. We demonstrate a reduced training effect when eyeball signal is regressed out of the data and reproduce the artifact with block design voluntary eye movement. Further, using independent components analysis on historical data, we find the artifact is common in BOLD data, but typically not task-correlated, even in tasks where one might expect differing amounts of eye movement in the active task blocks. The artifact, thus, does not significantly impact group results in typical fMRI experiments. Finally, we demonstrate this particular artifact can be avoided in rtfMRI experiments by ensuring that the phase encoding direction does not project any eye movement related artifact onto the ROI being used for feedback training. Our findings underscore the importance of taking great care in designing rtfMRI feedback procedures to avoid contamination with nonneuronal sources of BOLD signal alteration.

Functional connectivity of dorsolateral prefrontal cortex predicts cocaine relapse: implications for neuromodulation treatment.

Relapse is one of the most perplexing problems of addiction. The dorsolateral prefrontal cortex is crucially involved in numerous cognitive and affective processes that are implicated in the phenotypes of both substance use disorders and other neuropsychiatric diseases and has become the principal site to deliver transcranial magnetic stimulation for their treatment. However, the dorsolateral prefrontal cortex is an anatomically large and functionally heterogeneous region, and the specific dorsolateral prefrontal cortex locus and dorsolateral prefrontal cortex-based functional circuits that contribute to drug relapse and/or treatment outcome remain unknown. We systematically investigated the relationship of cocaine relapse with functional circuits from 98 dorsolateral prefrontal cortex regions-of-interest defined by evenly sampling the entire surface of bilateral dorsolateral prefrontal cortex in a cohort of cocaine dependent patients (n = 43, 5 Fr) following a psychosocial treatment intervention. Cox regression models were utilized to predict relapse likelihood based on dorsolateral prefrontal cortex functional connectivity strength. Functional connectivity from only 3 of the 98 dorsolateral prefrontal cortex loci, one in the left and two in the right hemisphere, significantly predicted cocaine relapse with an accuracy of 83.9%, 84.6% and 85.4%, respectively. Combining all three loci significantly improved prediction validity to 87.5%. Protective and risk circuits related to these dorsolateral prefrontal cortex loci were identified that have previously been implicated to support 'bottom up' drive to use drug and 'top down' control over behaviour together with social emotional, learning and memory processing. Three dorsolateral prefrontal cortex-centric circuits were identified that predict relapse to cocaine use with high accuracy. These functionally distinct dorsolateral prefrontal cortex-based circuits provide insights into the multiple roles played by the dorsolateral prefrontal cortex in cognitive and affective functioning that affects treatment outcome. The identified dorsolateral prefrontal cortex loci may serve as potential neuromodulation targets to be tested in subsequent clinical studies for addiction treatment and as clinically relevant biomarkers of its efficacy. Zhai et al. identify three dorsolateral prefrontal cortex (dlPFC)-centric circuits that predict cocaine relapse with high accuracy, providing insights into the multiple roles of the dlPFC in brain functioning that affects treatment outcome and suggesting the dlPFC loci as potential neuromodulation targets for addiction treatment.