Elliot Stein, Ph.D.

@article{Zhai2021,

title = {Dorsolateral prefrontal cortical circuits predict cocaine relapse: Implications for neuromodulation treatment. },

author = {T Zhai and H Gu and BJ Salmeron and B Adinoff and EA Stein and Y Yang},

year  = {2021},

date = {2021-05-22},

journal = {Brain Communications},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}

@article{Jedema:2021aa,

title = {Long-Term Cocaine Self-administration Produces Structural Brain Changes That Correlate With Altered Cognition},

author = {Hank P Jedema and Xiaowei Song and Howard J Aizenstein and Alexandra R Bonner and Elliot A Stein and Yihong Yang and Charles W Bradberry},

url = {https://pubmed.ncbi.nlm.nih.gov/33012519/},

doi = {10.1016/j.biopsych.2020.08.008},

isbn = {0006-3223},

year  = {2021},

date = {2021-02-15},

booktitle = {Biological Psychiatry},

journal = {Biological Psychiatry},

volume = {89},

number = {4},

pages = {376--385},

publisher = {Elsevier},

abstract = {BackgroundAn enduring question from cross-sectional clinical studies is whether the structural and functional differences often observed between cocaine users and healthy control subjects result from a history of drug use or instead reflect preexisting differences. To assess causality from drug exposure, true predrug baseline imaging and neurocognitive assessments are needed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Cover:2021aab,

title = {Whole brain dynamics during optogenetic self-stimulation of the medial prefrontal cortex in mice},

author = {Christopher G Cover and Andrew J Kesner and Shehzad Ukani and Elliot A Stein and Satoshi Ikemoto and Yihong Yang and Hanbing Lu},

url = {https://pubmed.ncbi.nlm.nih.gov/33446857/},

doi = {10.1038/s42003-020-01612-x},

isbn = {2399-3642},

year  = {2021},

date = {2021-01-01},

urldate = {2021-01-01},

journal = {Communications Biology},

volume = {4},

number = {1},

pages = {66},

abstract = {Intracranial self-stimulation, in which an animal performs an operant response to receive regional brain electrical stimulation, is a widely used procedure to study motivated behavior. While local neuronal activity has long been measured immediately before or after the operant, imaging the whole brain in real-time remains a challenge. Herein we report a method that permits functional MRI (fMRI) of brain dynamics while mice are cued to perform an operant task: licking a spout to receive optogenetic stimulation to the medial prefrontal cortex (MPFC) during a cue ON, but not cue OFF. Licking during cue ON results in activation of a widely distributed network consistent with underlying MPFC projections, while licking during cue OFF (without optogenetic stimulation) leads to negative fMRI signal in brain regions involved in acute extinction. Noninvasive whole brain readout combined with circuit-specific neuromodulation opens an avenue for investigating adaptive behavior in both healthy and disease models.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Tsai:kq,

title = {Converging structural and functional evidence for a rat salience network},

author = {Pei-Jung Tsai and Robin J Keeley and Stephanie A Carmack and Janaina C M Vendruscolo and Hanbing Lu and Hong Gu and Leandro F Vendruscolo and George F Koob and Ching-Po Lin and Elliot A Stein and Yihong Yang},

url = {https://doi.org/10.1016/j.biopsych.2020.06.023},

isbn = {0006-3223},

year  = {2020},

date = {2020-06-24},

urldate = {2020-06-24},

booktitle = {Biological Psychiatry},

journal = {Biological Psychiatry},

publisher = {Elsevier},

abstract = {Background

The salience network (SN) is dysregulated in many neuropsychiatric disorders, including substance use disorder. Initially described in humans, identification of a rodent SN would provide the ability to mechanistically interrogate this network in preclinical models of neuropsychiatric disorders.



Methods

We used modularity analysis on resting-state functional MRI data of rats (n=32) to parcellate rat insula into functional subdivisions and to identify a potential rat SN based on functional connectivity patterns from the insular subdivisions. We then used mouse tract tracing data from the Allen brain atlas to confirm the network’s underlying structural connectivity. We next compared functional connectivity profiles of the SN across rat, marmoset (n=10) and humans (n=30). Finally, we assessed rat SN’s response to conditioned cues in rats (n=21) with a history of heroin self-administration.



Results

We identified a putative rat SN, which consists of primarily the ventral anterior insula and anterior cingulate cortex, based on functional connectivity patterns from the ventral anterior insular division. Functional connectivity architecture of the rat SN is supported by the mouse neuronal tracer data. Moreover, the anatomical profile of the identified rat SN is similar to that of non-human primates and humans. Finally, we demonstrate that the rat SN responds to conditioned cues and increases functional connectivity to the Default Mode Network during conditioned heroin withdrawal.



Conclusions

The neurobiological identification of a rat SN together with a demonstration of its functional relevance provides a novel platform with which to interrogate its functional significance in normative and neuropsychiatric disease models.

},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lesage:2020aa,

title = {Nicotine dependence (trait) and acute nicotinic stimulation (state) modulate attention but not inhibitory control: converging fMRI evidence from the Go-Nogo and Flanker tasks.},

author = {E Lesage and M T Sutherland and T J Ross and B J Salmeron and E A Stein},

url = {https://www.ncbi.nlm.nih.gov/pubmed/31995811},

doi = {10.1038/s41386-020-0623-1},

issn = {1740-634X (Electronic); 0893-133X (Linking)},

year  = {2020},

date = {2020-01-29},

journal = {Neuropsychopharmacology},

address = {Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.},

abstract = {Cognitive deficits during nicotine withdrawal may contribute to smoking relapse. However, interacting effects of chronic nicotine dependence and acute nicotine withdrawal on cognitive control are poorly understood. Here we examine the effects of nicotine dependence (trait; smokers (n = 24) vs. non-smoking controls; n = 20) and acute nicotinic stimulation (state; administration of nicotine and varenicline, two FDA-approved smoking cessation aids, during abstinence), on two well-established tests of inhibitory control, the Go-Nogo task and the Flanker task, during fMRI scanning. We compared performance and neural responses between these four pharmacological manipulations in a double-blind, placebo-controlled crossover design. As expected, performance in both tasks was modulated by nicotine dependence, abstinence, and pharmacological manipulation. However, effects were driven entirely by conditions that required less inhibitory control. When demand for inhibitory control was high, abstinent smokers showed no deficits. By contrast, acutely abstinent smokers showed performance deficits in easier conditions and missed more trials. Go-Nogo fMRI results showed decreased inhibition-related neural activity in right anterior insula and right putamen in smokers and decreased dorsal anterior cingulate cortex activity on nicotine across groups. No effects were found on inhibition-related activity during the Flanker task or on error-related activity in either task. Given robust nicotinic effects on physiology and behavioral deficits in attention, we are confident that pharmacological manipulations were effective. Thus findings fit a recent proposal that abstinent smokers show decreased ability to divert cognitive resources at low or intermediate cognitive demand, while performance at high cognitive demand remains relatively unaffected, suggesting a primary attentional deficit during acute abstinence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{FISCHELL2020,

title = {Transcranial Direct Current Stimulation Applied to the Dorsolateral and Ventromedial Prefrontal Cortices in Smokers Modifies Cognitive Circuits Implicated in the Nicotine Withdrawal Syndrome},

author = {Sarah Aronson Fischell and Thomas J Ross and Zhi-De Deng and Betty Jo Salmeron and Elliot A Stein},

url = {http://www.sciencedirect.com/science/article/pii/S2451902220300173},

doi = {https://doi.org/10.1016/j.bpsc.2019.12.020},

issn = {2451-9022},

year  = {2020},

date = {2020-01-13},

urldate = {2020-01-13},

journal = {Biological Psychiatry: Cognitive Neuroscience and Neuroimaging},

abstract = {Background 

The Nicotine Withdrawal Syndrome remains a major impediment to smoking cessation. Cognitive and affective disturbances are associated with altered connectivity within and between the Executive Control Network (ECN), Default Mode Network (DMN), and Salience Network. We hypothesized that functional activity in cognitive control networks, and downstream amygdala circuits, would be modified by application of transcranial direct current stimulation (tDCS) to the left (L) dorsolateral prefrontal cortex (dlPFC, ECN) and right (R) ventromedial prefrontal cortex (vmPFC, DMN). 

Methods 

15 smokers (7 women) and 28 matched nonsmokers (14 women) participated in a randomized, sham-controlled, double-blind, exploratory crossover study of three tDCS conditions: Anodal-(L)dlPFC/Cathodal-(R)vmPFC, reversed polarity, and sham. Cognitive tasks probed withdrawal-related constructs (error monitoring; working memory; amygdala reactivity), while simultaneous fMRI measured brain activity. We assessed tDCS impact on trait (nonsmokers vs. sated-smokers) and state (sated vs abstinent) smoking aspects. 

Results 

Single-session, Anodal-(L)dlPFC/Cathodal-(R)vmPFC tDCS enhanced deactivation of DMN nodes during the working memory task and strengthened anterior cingulate cortex activity during the error monitoring task. Smokers were more responsive to tDCS-induced DMN deactivation when sated (vs. withdrawn), and displayed greater cingulate activity during error monitoring than nonsmokers. Nicotine withdrawal reduced task engagement and attention, and reduced suppression of DMN nodes. 

Conclusions 

Cognitive circuit dysregulation associated with nicotine withdrawal may be modifiable by anodal tDCS applied to L-dlPFC and cathodal tDCS applied to R-vmPFC. tDCS may have stronger effects as a complement to existing therapies, such as nicotine replacement, due to possible enhanced plasticity in the sated state. (NCT01511614, https://clinicaltrials.gov/).},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{FEDOTA2020b,

title = {Time-Varying Functional Connectivity Decreases as a Function of Acute Nicotine Abstinence},

author = {John R Fedota and Thomas J Ross and Juan Castillo and Michael R McKenna and Allison L Matous and Betty Jo Salmeron and Vinod Menon and Elliot A Stein},

url = {https://pubmed.ncbi.nlm.nih.gov/33436331/},

doi = {https://doi.org/10.1016/j.bpsc.2020.10.004},

issn = {2451-9022},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Biological Psychiatry: Cognitive Neuroscience and Neuroimaging},

abstract = {\textbf{Background}

The nicotine withdrawal syndrome (NWS) includes affective and cognitive disruptions whose incidence and severity vary across time during acute abstinence. However, most network-level neuroimaging uses static measures of resting-state functional connectivity and assumes time-invariance and is thus unable to capture dynamic brain-behavior relationships. Recent advances in resting-state functional connectivity signal processing allow characterization of time-varying functional connectivity (TVFC), which characterizes network communication between networks that reconfigure over the course of data collection. Therefore, TVFC may more fully describe network dysfunction related to the NWS. 



\textbf{Methods}

To isolate alterations in the frequency and diversity of communication across network boundaries during acute nicotine abstinence, we scanned 25 cigarette smokers in the nicotine-sated and abstinent states and applied a previously validated method to characterize TVFC at a network and a nodal level within the brain. 



\textbf{Results}

During abstinence, we found brain-wide decreases in the frequency of interactions between network nodes in different modular communities (i.e., temporal flexibility). In addition, within a subset of the networks examined, the variability of these interactions across community boundaries (i.e., spatiotemporal diversity) also decreased. Finally, within 2 of these networks, the decrease in spatiotemporal diversity was significantly related to NWS clinical symptoms. 



\textbf{Conclusions}

Using multiple measures of TVFC in a within-subjects design, we characterized a novel set of changes in network communication and linked these changes to specific behavioral symptoms of the NWS. These reductions in TVFC provide a meso-scale network description of the relative inflexibility of specific large-scale brain networks during acute abstinence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Abulseoud:2020aa,

title = {Short-term nicotine deprivation alters dorsal anterior cingulate glutamate concentration and concomitant cingulate-cortical functional connectivity},

author = {Osama A Abulseoud and Thomas J Ross and Hyung Wook Nam and Elisabeth C Caparelli and Michael Tennekoon and Brooke Schleyer and Juan Castillo and John Fedota and Hong Gu and Yihong Yang and Elliot Stein},

url = {https://pubmed.ncbi.nlm.nih.gov/32559759/},

doi = {10.1038/s41386-020-0741-9},

isbn = {1740-634X},

year  = {2020},

date = {2020-01-01},

urldate = {2020-01-01},

journal = {Neuropsychopharmacology},

volume = {45},

number = {11},

pages = {1920--1930},

abstract = {Most cigarette smokers who wish to quit too often relapse within the first few days of abstinence, primarily due to the aversive aspects of the nicotine withdrawal syndrome (NWS), which remains poorly understood. Considerable research has suggested that the dorsal anterior cingulate cortex (dACC) plays a key role in nicotine dependence, with its functional connections between other brain regions altered as a function of trait addiction and state withdrawal. The flow of information between dACC and fronto-striatal regions is secured through different pathways, the vast majority of which are glutamatergic. As such, we investigated dACC activity using resting state functional connectivity (rsFC) with functional magnetic resonance imaging (fMRI) and glutamate (Glu) concentration with magnetic resonance spectroscopy (MRS). We also investigated the changes in adenosine levels in plasma during withdrawal as a surrogate for brain adenosine, which plays a role in fine-tuning synaptic glutamate transmission. Using a double-blind, placebo-controlled, randomized crossover design, nontreatment seeking smoking participants (N = 30) completed two imaging sessions, one while nicotine sated and another after 36 h nicotine abstinence. We observed reduced dACC Glu (P = 0.029) along with a significant reduction in plasma adenosine (P = 0.03) and adenosine monophosphate (AMP; P < 0.0001) concentrations during nicotine withdrawal in comparison with nicotine sated state. This withdrawal state manipulation also led to an increase in rsFC strength (P < 0.05) between dACC and several frontal cortical regions, including left superior frontal gyrus (LSFG), and right middle frontal gyrus (RMFG). Moreover, the state-trait changes in dACC Glu and rsFC strength between the dACC and both SFG and MFG were positively correlated (P = 0.012, and P = 0.007, respectively). Finally, the change in circuit strength between dACC and LSFG was negatively correlated with the change in withdrawal symptom manifestations as measured by the Wisconsin Smoking Withdrawal Scale (P = 0.04) and Tobacco Craving Questionnaire (P = 0.014). These multimodal imaging-behavioral findings reveal the complex cascade of changes induced by acute nicotine deprivation and call for further investigation into the potential utility of adenosine- and glutamate-signaling as novel therapeutic targets to treat the NWS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Keeley:2020aa,

title = {Intrinsic differences in insular circuits moderate the negative association between nicotine dependence and cingulate-striatal connectivity strength},

author = {Robin J Keeley and Li-Ming Hsu and Julia K Brynildsen and Hanbing Lu and Yihong Yang and Elliot A Stein},

url = {https://pubmed.ncbi.nlm.nih.gov/32053829/},

doi = {10.1038/s41386-020-0635-x},

isbn = {1740-634X},

year  = {2020},

date = {2020-01-01},

journal = {Neuropsychopharmacology},

volume = {45},

number = {6},

pages = {1042--1049},

abstract = {The development of brain-based biomarkers to assess nicotine dependence severity and treatment efficacy are essential to improve the current marginally effective treatment outcomes. Cross-sectional resting state functional connectivity (rsFC) studies in humans identified a circuit between the dorsal anterior cingulate cortex and the ventral striatum that negatively correlated with increased nicotine dependence severity but was unaffected by acute nicotine administration, suggesting a trait marker of addiction. However, whether this trait circuit dysregulation is predispositional to or resultant from nicotine dependence is unclear. Using a rat model of nicotine dependence with longitudinal fMRI measurements, we assessed the relationship between ACC-striatal rsFC and nicotine dependence severity. Data-driven modularity-based parcellation of the rat medial prefrontal cortex (mPFC) combined with seed-based connectivity analysis with the striatum recapitulated the cingulate-striatum relationship observed in humans. Furthermore, the relationship between cingulate-striatal brain circuits and nicotine dependence severity as indexed by the intensity of precipitated withdrawal, was fully statistically moderated by a predispositional insular-frontal cortical functional circuit. These data suggest that the identified trans-species ACC-striatal circuit relationship with nicotine dependence severity is dysregulated following chronic nicotine administration-induced dependence and may be biased by individual differences in predispositional insula-based striatal-frontal circuits, highlighting the circuit's potential as a biomarker of dependence severity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Flannery:2019aa,

title = {Habenular and striatal activity during performance feedback are differentially linked with state-like and trait-like aspects of tobacco use disorder.},

author = {Jessica S Flannery and Michael C Riedel and Ranjita Poudel and Angela R Laird and Thomas J Ross and Betty Jo Salmeron and Elliot A Stein and Matthew T Sutherland},

url = {https://www.ncbi.nlm.nih.gov/pubmed/31633021},

doi = {10.1126/sciadv.aax2084},

issn = {2375-2548 (Electronic); 2375-2548 (Linking)},

year  = {2019},

date = {2019-10-09},

urldate = {2019-10-09},

journal = {Sci Adv},

volume = {5},

number = {10},

pages = {eaax2084},

address = {Department of Psychology, Florida International University, Miami, FL, USA.},

abstract = {The habenula, an epithalamic nucleus involved in reward and aversive processing, may contribute to negative reinforcement mechanisms maintaining nicotine use. We used a performance feedback task that differentially activates the striatum and habenula and administered nicotine and varenicline (versus placebos) to overnight-abstinent smokers and nonsmokers to delineate feedback-related functional brain alterations both as a function of smoking trait (smokers versus nonsmokers) and drug administration state (drug versus placebo). Smokers showed less striatal responsivity to positive feedback, an alteration not mitigated by drug administration, but rather correlated with trait-level addiction severity. Conversely, nicotine administration reduced habenula activity following both positive and negative feedback among abstinent smokers, but not nonsmokers, and increased habenula activity among smokers correlated with elevated state-level tobacco cravings. These outcomes highlight a dissociation between neurobiological processes linked with the dependence severity trait and the nicotine withdrawal state. Interventions simultaneously targeting both aspects may improve currently poor cessation outcomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hsu:2019aa,

title = {Intrinsic Insular-Frontal Networks Predict Future Nicotine Dependence Severity.},

author = {Li-Ming Hsu and Robin J Keeley and Xia Liang and Julia K Brynildsen and Hanbing Lu and Yihong Yang and Elliot A Stein},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30992371},

doi = {10.1523/JNEUROSCI.0140-19.2019},

issn = {1529-2401 (Electronic); 0270-6474 (Linking)},

year  = {2019},

date = {2019-06-19},

journal = {J Neurosci},

volume = {39},

number = {25},

pages = {5028--5037},

address = {Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, and.},

abstract = {Although 60% of the US population have tried smoking cigarettes, only 16% smoke regularly. Identifying this susceptible subset of the population before the onset of nicotine dependence may encourage targeted early interventions to prevent regular smoking and/or minimize severity. While prospective neuroimaging in human populations can be challenging, preclinical neuroimaging models before chronic nicotine administration can help to develop translational biomarkers of disease risk. Chronic, intermittent nicotine (0, 1.2, or 4.8 mg/kg/d; N = 10-11/group) was administered to male Sprague Dawley rats for 14 d; dependence severity was quantified using precipitated withdrawal behaviors collected before, during, and following forced nicotine abstinence. Resting-state fMRI functional connectivity (FC) before drug administration was subjected to a graph theory analytical framework to form a predictive model of subsequent individual differences in nicotine dependence. Whole-brain modularity analysis identified five modules in the rat brain. A metric of intermodule connectivity, participation coefficient, of an identified insular-frontal cortical module predicted subsequent dependence severity, independent of nicotine dose. To better spatially isolate this effect, this module was subjected to a secondary exploratory modularity analysis, which segregated it into three submodules (frontal-motor, insular, and sensory). Higher FC among these three submodules and three of the five originally identified modules (striatal, frontal-executive, and sensory association) also predicted dependence severity. These data suggest that predispositional, intrinsic differences in circuit strength between insular-frontal-based brain networks before drug exposure may identify those at highest risk for the development of nicotine dependence.SIGNIFICANCE STATEMENT Developing biomarkers of individuals at high risk for addiction before the onset of this brain-based disease is essential for prevention, early intervention, and/or subsequent treatment decisions. Using a rodent model of nicotine dependence and a novel data-driven, network-based analysis of resting-state fMRI data collected before drug exposure, functional connections centered on an intrinsic insular-frontal module predicted the severity of nicotine dependence after drug exposure. The predictive capacity of baseline network measures was specific to inter-regional but not within-region connectivity. While insular and frontal regions have consistently been implicated in nicotine dependence, this is the first study to reveal that innate, individual differences in their circuit strength have the predictive capacity to identify those at greatest risk for and resilience to drug dependence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Hu:2019aa,

title = {Compulsive drug use is associated with imbalance of orbitofrontal- and prelimbic-striatal circuits in punishment-resistant individuals.},

author = {Yuzheng Hu and Betty Jo Salmeron and Irina N Krasnova and Hong Gu and Hanbing Lu and Antonello Bonci and Jean L Cadet and Elliot A Stein and Yihong Yang},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30988198},

doi = {10.1073/pnas.1819978116},

issn = {1091-6490 (Electronic); 0027-8424 (Linking)},

year  = {2019},

date = {2019-04-30},

urldate = {2019-04-30},

journal = {Proc Natl Acad Sci U S A},

volume = {116},

number = {18},

pages = {9066--9071},

address = {Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Programs, National Institutes of Health, Baltimore, MD 21224; yihongyang@intra.nida.nih.gov huyuzheng@zju.edu.cn.},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Carmack:2019aa,

title = {Heroin addiction engages negative emotional learning brain circuits in rats.},

author = {Stephanie A Carmack and Robin J Keeley and Janaina Cm Vendruscolo and Emily G Lowery-Gionta and Hanbing Lu and George F Koob and Elliot A Stein and Leandro F Vendruscolo},

url = {https://www.ncbi.nlm.nih.gov/pubmed/30913040},

doi = {10.1172/JCI125534},

issn = {1558-8238 (Electronic); 0021-9738 (Linking)},

year  = {2019},

date = {2019-03-26},

journal = {J Clin Invest},

volume = {130},

abstract = {Opioid use disorder (OUD) is associated with the emergence of persistent negative emotional states during drug abstinence that drive compulsive drug taking and seeking. Functional magnetic resonance imaging (fMRI) in rats identified neurocircuits that were activated by stimuli that were previously paired with heroin withdrawal. The activation of amygdala and hypothalamic circuits was related to the degree of heroin dependence, supporting the significance of conditioned negative affect in sustaining compulsive-like heroin seeking and taking and providing neurobiological insights into the drivers of the current opioid crisis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Ding:2019aa,

title = {Evidence of subgroups in smokers as revealed in clinical measures and evaluated by neuroimaging data: a preliminary study.},

author = {Xiaoyu Ding and Betty Jo Salmeron and Jamei Wang and Yihong Yang and Elliot A Stein and Thomas J Ross},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29516603},

doi = {10.1111/adb.12620},

issn = {1369-1600 (Electronic); 1355-6215 (Linking)},

year  = {2018},

date = {2018-03-08},

urldate = {2018-03-08},

journal = {Addict Biol},

volume = {24},

number = {4},

pages = {777--786},

address = {Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Fedota:2018aa,

title = {Nicotine Abstinence Influences the Calculation of Salience in Discrete Insular Circuits.},

author = {John R Fedota and Xiaoyu Ding and Allison L Matous and Betty Jo Salmeron and Michael R McKenna and Hong Gu and Thomas J Ross and Elliot A Stein},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29529410},

doi = {10.1016/j.bpsc.2017.09.010},

issn = {2451-9030 (Electronic); 2451-9022 (Linking)},

year  = {2018},

date = {2018-02-01},

urldate = {2018-02-01},

journal = {Biol Psychiatry Cogn Neurosci Neuroimaging},

volume = {3},

number = {2},

pages = {150--159},

address = {Neuroimaging Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland. Electronic address: john.fedota@nih.gov.},

abstract = {BACKGROUND: Insular subdivisions show distinct patterns of resting-state functional connectivity (rsFC) with specific brain regions, each with different functional significance. Seeds in these subdivisions are employed to characterize the effects of acute nicotine abstinence on rsFC between insula subdivisions and brain networks implicated in addiction and attentional control. METHODS: In a within-subjects design, resting-state blood oxygen level-dependent data were collected from treatment-seeking smokers (N= 20) following smoking satiety and again following 48 hours of nicotine abstinence. Three right hemisphere insular regions of interest (dorsal, ventral, and posterior) served as seeds for analyses. Indices of both static and dynamic rsFC were obtained and correlated with indices of subjective withdrawal and behavioral performance. RESULTS: Abstinence-induced physiological, subjective, and cognitive differences were observed. Overall dynamic rsFC was reduced during abstinence, and circuits containing each insular seed showed changes in rsFC as a function of nicotine abstinence. Specifically, dorsal and posterior insular connections to the default mode and salience networks were enhanced, while a previously undescribed ventral insular connection to the executive control network was reduced. Further, static rsFC was significantly correlated with subjective ratings of aversive affect and withdrawal in the modified ventral and posterior insular-seeded circuits. CONCLUSIONS: As predicted, divergent connections between insula subdivisions and anticorrelated resting brain networks were observed during abstinence. These changes reflect an attentional bias toward aversive affective processing and not directly away from exogenous cognitive processing, suggesting a coordinated modulation of circuits associated with interoceptive and affective processing that instantiates an aversive state during nicotine abstinence.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Sutherland:2018aa,

title = {Functional Neurocircuits and Neuroimaging Biomarkers of Tobacco Use Disorder.},

author = {Matthew T Sutherland and Elliot A Stein},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29398401},

doi = {10.1016/j.molmed.2017.12.002},

issn = {1471-499X (Electronic); 1471-4914 (Linking)},

year  = {2018},

date = {2018-02-01},

urldate = {2018-02-01},

journal = {Trends Mol Med},

volume = {24},

number = {2},

pages = {129--143},

address = {Department of Psychology, Florida International University, Miami, FL, USA.},

abstract = {Drug abuse and addiction remain major public health issues, exemplified by the opioid epidemic currently devastating the United States. Treatment outcomes across substance use disorders remain unacceptably poor, wherein drug discovery/development for this multifaceted neuropsychiatric disorder focuses on single molecular-level targets. Rather, our opinion is that a systems-level neuroimaging perspective is crucial for identifying novel therapeutic targets, biomarkers to stratify patients, and individualized treatment strategies. Focusing on tobacco use disorder, we advocate a brain systems-level perspective linking two abuse-related facets (i.e., statelike withdrawal and traitlike addiction severity) with specific neurocircuitry (insula- and striatum-centered networks). To the extent that precise neurocircuits mediate distinct facets of abuse, treatment development must adopt not only a systems-level perspective, but also multi-intervention rather than mono-intervention practices.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Lesage2017,

title = {Neural Signatures of Cognitive Flexibility and Reward Sensitivity Following Nicotinic Receptor Stimulation in Dependent Smokers: A Randomized Trial.},

author = {Elise Lesage and Sarah E Aronson and Matthew T Sutherland and Thomas J Ross and Betty Jo Salmeron and Elliot A Stein},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28403383},

doi = {10.1001/jamapsychiatry.2017.0400},

issn = {2168-6238 (Electronic); 2168-622X (Linking)},

year  = {2017},

date = {2017-06-01},

journal = {JAMA Psychiatry},

volume = {74},

number = {6},

pages = {632--640},

address = {Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland.},

abstract = {Importance: Withdrawal from nicotine is an important contributor to smoking relapse. Understanding how reward-based decision making is affected by abstinence and by pharmacotherapies such as nicotine replacement therapy and varenicline tartrate may aid cessation treatment. Objective: To independently assess the effects of nicotine dependence and stimulation of the nicotinic acetylcholine receptor on the ability to interpret valence information (reward sensitivity) and subsequently alter behavior as reward contingencies change (cognitive flexibility) in a probabilistic reversal learning task. Design, Setting, and Participants: Nicotine-dependent smokers and nonsmokers completed a probabilistic reversal learning task during acquisition of functional magnetic resonance imaging (fMRI) in a 2-drug, double-blind placebo-controlled crossover design conducted from January 21, 2009, to September 29, 2011. Smokers were abstinent from cigarette smoking for 12 hours for all sessions. In a fully Latin square fashion, participants in both groups underwent MRI twice while receiving varenicline and twice while receiving a placebo pill, wearing either a nicotine or a placebo patch. Imaging analysis was performed from June 15, 2015, to August 10, 2016. Main Outcome and Measures: A well-established computational model captured effects of smoking status and administration of nicotine and varenicline on probabilistic reversal learning choice behavior. Neural effects of smoking status, nicotine, and varenicline were tested for on MRI contrasts that captured reward sensitivity and cognitive flexibility. Results: The study included 24 nicotine-dependent smokers (12 women and 12 men; mean [SD] age, 35.8 [9.9] years) and 20 nonsmokers (10 women and 10 men; mean [SD] age, 30.4 [7.2] years). Computational modeling indicated that abstinent smokers were biased toward response shifting and that their decisions were less sensitive to the available evidence, suggesting increased impulsivity during withdrawal. These behavioral impairments were mitigated with nicotine and varenicline. Similarly, decreased mesocorticolimbic activity associated with cognitive flexibility in abstinent smokers was restored to the level of nonsmokers following stimulation of nicotinic acetylcholine receptors (familywise error-corrected P < .05). Conversely, neural signatures of decreased reward sensitivity in smokers (vs nonsmokers; familywise error-corrected P < .05) in the dorsal striatum and anterior cingulate cortex were not mitigated by nicotine or varenicline. Conclusions and Relevance: There was a double dissociation between the effects of chronic nicotine dependence on neural representations of reward sensitivity and acute effects of stimulation of nicotinic acetylcholine receptors on behavioral and neural signatures of cognitive flexibility in smokers. These chronic and acute pharmacologic effects were observed in overlapping mesocorticolimbic regions, suggesting that available pharmacotherapies may alleviate deficits in the same circuitry for certain mental computations but not for others. Trial Registration: clinicaltrials.gov Identifier: NCT00830739.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Geng2017,

title = {Salience and default mode network dysregulation in chronic cocaine users predict treatment outcome.},

author = {Xiujuan Geng and Yuzheng Hu and Hong Gu and Betty Jo Salmeron and Bryon Adinoff and Elliot A Stein and Yihong Yang},

url = {https://www.ncbi.nlm.nih.gov/pubmed/28334915},

doi = {10.1093/brain/awx036},

issn = {1460-2156 (Electronic); 0006-8950 (Linking)},

year  = {2017},

date = {2017-05-01},

journal = {Brain},

volume = {140},

number = {5},

pages = {1513--1524},

address = {Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}