Intrinsic differences in insular circuits moderate the negative association between nicotine dependence and cingulate-striatal connectivity strength.
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ABSTRACT:
SUBMITTER: Keeley RJ
PROVIDER: S-EPMC7162949 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Schizophrenia (SZ) is associated with high rates of smoking. We previously found that resting state functional connectivity (rsFC) between the dorsal anterior cingulate (dACC) and striatum is independently associated with nicotine addiction and psychiatric illness. Since the insula is implicated in nicotine dependence, we hypothesized that SZ smokers will have greater dysfunction in smoking-related insular and dACC circuits than normal control smokers (NC) independent of smoking severity, consistent with an inherent disease-related weakening of smoking-related circuits. Nicotine challenge was used to demonstrate that decreased rsFC in identified circuits reflects addiction trait and is not affected by pharmacological state. Twenty-four NC smokers and 20 smokers with SZ matched on nicotine addiction severity participated in a resting state fMRI study and were scanned during two separate sessions while receiving a placebo or nicotine patch, in a randomized, cross-over design. Using individualized, anatomically defined anterior and posterior insula and dACC as regions of interest (ROI), whole brain rsFC was performed using each ROI as a seed. Significant negative correlations between smoking severity and rsFC between insula, dACC and striatum were found for both groups. Furthermore, smokers with SZ demonstrated additive reductions in circuit strength between the dACC and insula compared to NC smokers independent of smoking severity. Nicotine challenge did not significantly alter rsFC in insula-dACC-striatal circuits. Reduced rsFC strength between the insula, dACC and striatum is associated with nicotine addiction severity in both non-psychiatrically ill and in SZ smokers. Decreased insula-dACC rsFC may index overlapping circuitry associated with smoking and SZ.
| S-EPMC3502674 | biostudies-literature
Project description:Abstract Nicotine exposure is associated with regional changes in brain nicotinic acetylcholine receptors subtype expression patterns as a function of dose and age at the time of exposure. Moreover, nicotine dependence is associated with changes in brain circuit functional connectivity, but the relationship between such connectivity and concomitant regional distribution changes in nicotinic acetylcholine receptor subtypes following nicotine exposure is not understood. Although smoking typically begins in adolescence, developmental changes in brain circuits and nicotinic acetylcholine receptors following chronic nicotine exposure remain minimally investigated. Here, we combined in vitro nicotinic acetylcholine receptor autoradiography with resting state functional magnetic resonance imaging to measure changes in [3H]nicotine binding and α4ß2 subtype nicotinic acetylcholine receptor binding and circuit connectivity across the brain in adolescent (postnatal Day 33) and adult (postnatal Day 68) rats exposed to 6 weeks of nicotine administration (0, 1.2 and 4.8 mg/kg/day). Chronic nicotine exposure increased nicotinic acetylcholine receptor levels and induced discrete, developmental stage changes in regional nicotinic acetylcholine receptor subtype distribution. These effects were most pronounced in striatal, thalamic and cortical regions when nicotine was administered during adolescence but not in adults. Using these regional receptor changes as seeds, resting state functional magnetic resonance imaging identified dysregulations in cortico-striatal-thalamic-cortical circuits that were also dysregulated following adolescent nicotine exposure. Thus, nicotine-induced increases in cortical, striatal and thalamic nicotinic acetylcholine receptors during adolescence modifies processing and brain circuits within cortico-striatal-thalamic-cortical loops, which are known to be crucial for multisensory integration, action selection and motor output, and may alter the developmental trajectory of the adolescent brain. This unique multimodal study significantly advances our understanding of nicotine dependence and its effects on the adolescent brain. Keeley et al. present a multimodal study assessing changes in nicotinic receptor subtype expression and resting-state functional connectivity in adolescents and adults after chronic nicotine administration. Following exposure, differences in receptor density and resting-state functional connectivity were found in adolescents but not adults, particularly in the cortical, striatal and thalamic regions. Graphical Abstract Graphical abstract
| S-EPMC9683397 | biostudies-literature
Project description: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.
| S-EPMC5851477 | biostudies-literature
Project description: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.
| S-EPMC2922167 | biostudies-literature
Project description:Anxiety disorders are among the most common psychiatric disorders of adolescence. Behavioral and task-based imaging studies implicate altered reward system function, including striatal dysfunction, in adolescent anxiety. However, no study has yet examined alterations of the striatal intrinsic functional connectivity in adolescent anxiety disorders. The current study examines striatal intrinsic functional connectivity (iFC), using six bilateral striatal seeds, among 35 adolescents with anxiety disorders and 36 healthy comparisons. Anxiety is associated with abnormally low iFC within the striatum (e.g., between nucleus accumbens and caudate nucleus), and between the striatum and prefrontal regions, including subgenual anterior cingulate cortex, posterior insula and supplementary motor area. The current findings extend prior behavioral and task-based imaging research, and provide novel data implicating decreased striatal iFC in adolescent anxiety. Alterations of striatal neurocircuitry identified in this study may contribute to the perturbations in the processing of motivational, emotional, interoceptive, and motor information seen in pediatric anxiety disorders. This pattern of the striatal iFC perturbations can guide future research on specific mechanisms underlying anxiety.
| S-EPMC5107006 | biostudies-literature
Project description: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.
| S-EPMC7608204 | biostudies-literature
Project description:BackgroundVariation in the CYP2A6 gene alters the rate of nicotine metabolic inactivation and is associated with smoking behaviors and cessation success rates. The underlying neurobiological mechanisms of this genetic influence are unknown.MethodsIntrinsic functional connectivity strength, a whole-brain, data-driven, graph theory-based method, was applied to resting-state functional magnetic resonance imaging data in 66 smokers and 92 nonsmokers. A subset of subjects (n = 23/20; smokers/nonsmokers) performed the monetary incentive delay task, probing reward anticipation, and a go/no-go task, probing response inhibition, on two occasions, in the presence and absence of a nicotine patch.ResultsA significant CYP2A6 genotype × smoking effect was found in the dorsal anterior cingulate cortex and ventral striatum, such that the normal (vs. slow) genotype individuals showed greater functional connectivity strength among smokers but not nonsmokers. Functional connectivity strength was negatively associated with severity of nicotine dependence in slow metabolizers. Both hubs were biased by inputs from the insula identified from seed-based connectivity. Similar gene × environment interactions were seen in ventral striatum during smoking abstinence when subjects performed the monetary incentive delay task and in dorsal anterior cingulate cortex when they performed the go/no-go task; both reductions were "normalized" in smokers (and increased in nonsmokers) after acute nicotine administration.ConclusionsBecause the CYP2A6 effect was seen only in smokers, these data suggest that the rate of nicotine metabolism-and thus the concentration of nicotine presented to the brain over the course of nicotine addiction-shapes brain circuits that, among other functions, compute reward and impulsivity processes.
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Project description:To determine if methamphetamine-dependent (MD) individuals exhibit behavioral or neural processing differences in risk-taking relative to healthy comparison participants (CTL).This was a cross-sectional study comparing two groups' behavior on a risk-taking task and neural processing as assessed using functional magnetic resonance imaging (fMRI).The study was conducted in an in-patient treatment center and a research fMRI facility in the United States.Sixty-eight recently abstinent MD individuals recruited from a treatment program and 40 CTL recruited from the community completed the study.The study assessed risk-taking behavior (overall and post-loss) using the Risky Gains Task (RGT), sensation-seeking, impulsivity and blood-oxygenation-level-dependent activation in the brain during the decision phase of the RGT.Relative to CTL, MD displayed decreased activation in the bilateral rostral anterior cingulate cortex (ACC) and greater activation in the left insula across risky and safe decisions (P?<?0.05). Right mid-insula activation among CTL did not vary between risky and safe decisions, but among MD it was higher during risky relative to safe decisions (P?<?0.05). Among MD, lower activation in the right rostral ACC (r?=?-0.39, P?<?0.01) and higher activation in the right mid-insula (r?=?0.35, P?<?0.01) during risky decisions were linked to a higher likelihood of choosing a risky option following a loss.Methamphetamine-dependent individuals show disrupted risk-related processing in both anterior cingulate and insula, brain areas that have been implicated in cognitive control and interoceptive processing. Attenuated neural processing of risky options may lead to risk-taking despite experiencing negative consequences.
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Project description:Dopamine depletion in the putamen is associated with altered motor network functional connectivity in people with Parkinson's disease (PD), but the functional significance of these changes remains unclear, attributed to either pathological or compensatory mechanisms in different studies. Here, we examined the effects of PD on dorsal caudal putamen functional connectivity, off and on dopamine replacement therapy (DRT), using resting state fMRI. Motor performance was assessed with the Purdue pegboard task. Twenty-one patients with mild-moderate Parkinson's disease were studied twice, once after an overnight DRT washout and once after the administration of a standard dose of levodopa (Sinemet), and compared to 20 demographically-matched healthy control participants. PD patients off DRT showed increased putamen functional connectivity with both the cerebellum (lobule V) and primary motor cortex (M1), relative to healthy controls. Greater putamen-cerebellar functional connectivity was significantly correlated with better motor performance, whereas greater putamen-M1 functional connectivity was predictive of poorer motor performance. The administration of levodopa improved motor performance in the PD group, as expected, and reduced putamen-cerebellar connectivity to levels comparable to the healthy control group. The strength of putamen-cerebellar functional connectivity continued to predict motor performance in the PD group while on levodopa. These findings argue that increased putamen-M1 functional connectivity reflects a pathological change, deleterious to motor performance. In contrast, increased putamen-cerebellar connectivity reflects a compensatory mechanism.
| S-EPMC4669533 | biostudies-literature
Project description:Multiple, segregated fronto-cerebellar circuits have been characterized in nonhuman primates using transneuronal tracing techniques including those that target prefrontal areas. Here, we used functional connectivity MRI (fcMRI) in humans (n = 40) to identify 4 topographically distinct fronto-cerebellar circuits that target 1) motor cortex, 2) dorsolateral prefrontal cortex, 3) medial prefrontal cortex, and 4) anterior prefrontal cortex. All 4 circuits were replicated and dissociated in an independent data set (n = 40). Direct comparison of right- and left-seeded frontal regions revealed contralateral lateralization in the cerebellum for each of the segregated circuits. The presence of circuits that involve prefrontal regions confirms that the cerebellum participates in networks important to cognition including a specific fronto-cerebellar circuit that interacts with the default network. Overall, the extent of the cerebellum associated with prefrontal cortex included a large portion of the posterior hemispheres consistent with a prominent role of the cerebellum in nonmotor functions. We conclude by providing a provisional map of the topography of the cerebellum based on functional correlations with the frontal cortex.
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