Stacey L. Farmer

Insula–Dorsal Anterior Cingulate Cortex Coupling is Associated with Enhanced Brain Reactivity to Smoking Cues

The insula plays a critical role in maintaining nicotine dependence and reactivity to smoking cues. More broadly, the insula and the dorsal anterior cingulate cortex (dACC) are key nodes of the salience network (SN), which integrates internal and extrapersonal information to guide behavior. Thus, insula–dACC interactions may be integral in processing salient information such as smoking cues that facilitate continued nicotine use. We evaluated functional magnetic resonance imaging (fMRI) data from nicotine-dependent participants during rest, and again when they viewed smoking-related images. Greater insula–dACC coupling at rest was significantly correlated with enhanced smoking cue-reactivity in brain areas associated with attention and motor preparation, including the visual cortex, right ventral lateral prefrontal cortex, and the dorsal striatum. In an independent cohort, we found that insula–dACC connectivity was stable over 1-h delay and was not influenced by changes in subjective craving or expired carbon monoxide, suggesting that connectivity strength between these regions may be a trait associated with heightened cue-reactivity. Finally, we also showed that insula reactivity to smoking cues correlates with a rise in cue-reactivity throughout the entire SN, indicating that the insula’s role in smoking cue-reactivity is not functionally independent, and may actually represent the engagement of the entire SN. Collectively, these data provide a more network-level understanding of the insula’s role in nicotine dependence and shows a relationship between inherent brain organization and smoking cue-reactivity.

The isoflavone puerarin reduces alcohol intake in heavy drinkers: A pilot study

BACKGROUND Isoflavone compounds naturally occurring in the root of the kudzu plant have been used historically to treat alcohol-related problems. A pilot study was conducted to assess the effects of one primary isoflavone--puerarin--for its ability to modify alcohol intake in humans. METHODS Ten (10) healthy adult volunteers were administered puerarin (1200 mg daily) in a double-blind, placebo-controlled, crossover design experiment for one week prior to an afternoon drinking session lasting 1.5h. Participants had access to up to six bottles of their preferred brand of beer in addition to juice and water. A time course of drinking, sip volumes, and total amount consumed were recorded. RESULTS Participants consumed on average 3.5 (±0.55) beers when treated with placebo and 2.4 (±0.41) beers when treated with puerarin. In contrast to drinking following placebo treatment when 3 participants drank 5 beers and 1 participant drank all 6 beers, none drank 5 or 6 beers when treated with puerarin. Drinking topography also changed. When treated with puerarin, participants decreased sip size, took more sips to finish a beer, and took longer to consume each beer. Additionally, after finishing a beer, latency to opening the next beer was increased. CONCLUSIONS This study is the first demonstration that a single isoflavone found in the kudzu root can alter alcohol drinking in humans. These results suggest that alcohol consumption patterns are influenced by puerarin administration and this botanical medication may be a useful adjunct in the treatment of excessive alcohol intake.

Striatal Morphology is Associated with Tobacco Cigarette Craving

The striatum has a clear role in addictive disorders and is involved in drug-related craving. Recently, enhanced striatal volume was associated with greater lifetime nicotine exposure, suggesting a bridge between striatal function and structural phenotypes. To assess this link between striatal structure and function, we evaluated the relationship between striatal morphology and this brain region’s well-established role in craving. In tobacco smokers, we assessed striatal volume, surface area, and shape using a new segmentation methodology coupled with local shape indices. Striatal morphology was then related with two measures of craving: state-based craving, assessed by the brief questionnaire of smoking urges (QSU), and craving induced by smoking-related images. A positive association was found between left striatal volume and surface area with both measures of craving. A more specific relationship was found between both craving measures and the dorsal, but not in ventral striatum. Evaluating dorsal striatal subregions showed a single relationship between the caudate and QSU. Although cue-induced craving and the QSU were both associated with enlarged striatal volume and surface area, these measures were differentially associated with global or more local striatal volumes. We also report a connection between greater right striatal shape deformations and cue-induced craving. Shape deformations associated with cue-induced craving were specific to striatal subregions involved in habitual responding to rewarding stimuli, which is relevant given the habitual nature of cue-induced craving. The current findings confirm a relationship between striatal function and morphology and suggest that variation in striatal morphology may be a biomarker for craving severity.

An Increase in Tobacco Craving Is Associated with Enhanced Medial Prefrontal Cortex Network Coupling

Craving is a key aspect of drug dependence that is thought to motivate continued drug use. Numerous brain regions have been associated with craving, suggesting that craving is mediated by a distributed brain network. Whether an increase in subjective craving is associated with enhanced interactions among brain regions was evaluated using resting state functional magnetic imaging (fMRI) in nicotine dependent participants. We focused on craving-related changes in the orbital and medial prefrontal cortex (OMPFC) network, which also included the subgenual anterior cingulate cortex (sgACC) extending into the ventral striatum. Brain regions in the OMPFC network are not only implicated in addiction and reward, but, due to their rich anatomic interconnections, may serve as the site of integration across craving-related brain regions. Subjective craving and resting state fMRI were evaluated twice with an ∼1 hour delay between the scans. Cigarette craving was significantly increased at the end, relative to the beginning of the scan session. Enhanced craving was associated with heightened coupling between the OMPFC network and other cortical, limbic, striatal, and visceromotor brain regions that are both anatomically interconnected with the OMPFC, and have been implicated in addiction and craving. This is the first demonstration confirming that an increase in craving is associated with enhanced brain region interactions, which may play a role in the experience of craving.

GABA levels in the dorsal anterior cingulate cortex associated with difficulty ignoring smoking-related cues in tobacco-dependent volunteers.

Substance abusers have difficulty ignoring drug-related cues, which is associated with relapse vulnerability. This ‘attentional bias’ towards drug cues translates into an inability to ignore drug-related stimuli and may reflect deficits in the brain regions, such as the dorsal anterior cingulate cortex (dACC)—a key region in cognitive control and adaptive decision making. Quantifying relationships between attentional biases to drug cues and dACC neurochemistry could aid in identifying neurobiological mechanisms associated with increased relapse vulnerability precipitated by drug cues. As gamma-aminobutyric acid (GABA) deficits have been linked to impaired cognition and addictive disorders, we hypothesized that reduced GABA in the dACC would be associated with increased attentional biases towards smoking-related cues. We confirmed this hypothesis among nicotine-dependent tobacco smokers by combining an offline behavioral measure of attentional bias with magnetic resonance spectroscopy. Smokers with the greatest attentional bias also experienced more negative affect during early nicotine withdrawal. Findings revealed a relationship between heightened reactivity to drug cues, and both decreasing dACC GABA and early withdrawal symptoms. Because reduced GABA function in frontal brain regions disrupt cognitive function, our findings suggest that smokers with diminished dACC GABA may lack the cognitive resources to successfully ignore highly salient distractors such as tobacco-related stimuli and therefore might be more prone to cue-induced relapse. This newly discovered relationship between dACC GABA and attentional bias provides evidence for a neurochemical target, which may aid smoking cessation in highly cue-reactive individuals.

Memory retrieval of smoking-related images induce greater insula activation as revealed by an fMRI-based delayed matching to sample task.

Nicotine dependence is a chronic and difficult to treat disorder. While environmental stimuli associated with smoking precipitate craving and relapse, it is unknown whether smoking cues are cognitively processed differently than neutral stimuli. To evaluate working memory differences between smoking‐related and neutral stimuli, we conducted a delay‐match‐to‐sample (DMS) task concurrently with functional magnetic resonance imaging (fMRI) in nicotine‐dependent participants. The DMS task evaluates brain activation during the encoding, maintenance and retrieval phases of working memory. Smoking images induced significantly more subjective craving, and greater midline cortical activation during encoding in comparison to neutral stimuli that were similar in content yet lacked a smoking component. The insula, which is involved in maintaining nicotine dependence, was active during the successful retrieval of previously viewed smoking versus neutral images. In contrast, neutral images required more prefrontal cortex‐mediated active maintenance during the maintenance period. These findings indicate that distinct brain regions are involved in the different phases of working memory for smoking‐related versus neutral images. Importantly, the results implicate the insula in the retrieval of smoking‐related stimuli, which is relevant given the insulas emerging role in addiction.

Cigarette craving is associated with blunted reward processing in nicotine-dependent smokers

BACKGROUND Dysfunctional reward processing leading to the undervaluation of non-drug rewards is hypothesized to play a crucial role in nicotine dependence. However, it is unclear if blunted reward responsivity and the desire to use nicotine are directly linked after a brief period of abstinence. Such an association would suggest that individuals with reduced reward responsivity may be at increased risk to experience nicotine craving. METHODS Reward function was evaluated with a probabilistic reward task (PRT), which measures reward responsivity to monetary incentives. To identify whether smoking status influenced reward function, PRT performance was compared between non-depressed, nicotine-dependent smokers and non-smokers. Within smokers, correlations were conducted to determine if blunted reward responsivity on the PRT was associated with increased nicotine craving. Time since last nicotine exposure was standardized to 4h for all smokers. RESULTS Smokers and non-smokers did not differ in reward responsivity on the PRT. However, within smokers, a significant negative correlation was found between reward responsivity and intensity of nicotine craving. CONCLUSIONS The current findings show that, among smokers, the intensity of nicotine craving is linked to lower sensitivity to non-drug rewards. This finding is in line with prior theories that suggest reward dysfunction in some clinical populations (e.g., depressive disorders, schizophrenia) may facilitate nicotine use. The current study expands on such theories by indicating that sub-clinical variations in reward function are related to motivation for nicotine use. Identifying smokers who show blunted sensitivity to non-drug rewards may help guide treatments aimed at mitigating the motivation to smoke.

Multi-site exploration of sex differences in brain reactivity to smoking cues: Consensus across sites and methodologies

BACKGROUND Biological sex influences cigarette smoking behavior. More men than women smoke, but women have a harder time quitting. Sex differences in smoking cue (SC) reactivity may underlie such behavioral differences. However, the influence of sex on brain reactivity to SCs has yielded inconsistent findings suggesting the need for continued study. Here, we investigated the effect of sex on SC reactivity across two sites using different imaging modalities and SC stimulus types. METHODS Pseudo-continuous arterial spin-labeled (pCASL) perfusion functional magnetic resonance imaging (fMRI) was used to assess brain responses to SC versus non-SC videos in 40 smokers (23 females) at the University of Pennsylvania. BOLD fMRI was used to assess brain responses to SC versus non-SC still images in 32 smokers (18 females) at McLean Hospital. Brain reactivity to SCs was compared between men and women and was correlated with SC-induced craving. RESULTS In both cohorts, males showed higher SC versus non-SC reactivity compared to females in reward-related brain regions (i.e., ventral striatum/ventral pallidum, ventral medial prefrontal cortex). Brain activation during SC versus non-SC exposure correlated positively with SC-induced subjective craving in males, but not females. CONCLUSIONS The current work provides much needed replication and validation of sex differences in SC-reactivity. These findings also add to a body of literature showing that men have greater reward-related brain activation to drug cues across drug classes. Such sex differences confirm the need to consider sex not only when evaluating SC-reactivity but when examining nicotine dependence etiology and treatment.

Improved low-cost, MR-compatible olfactometer to deliver tobacco smoke odor

We describe a low-cost, MRI-compatible olfactometer that delivers fresh cigarette smoke odor, a challenging odorant to present, as well as other odorants. This new olfactometer retains all of the advantages of an earlier design that was capable of only delivering volatile odors (Lowen & Lukas, Behavior Research Methods, 38, 307–313, 2006). The new system incorporates a novel switching mechanism that allows it to deliver fresh smoke generated from a burning cigarette during a stimulus presentation paradigm that might be employed in a cue-reactivity experiment. An evaluation study established that the olfactometer reliably delivered smoke to the participants and that tobacco smoke was discriminated from other odorants; there were no adverse reactions to the device.

Early onset tobacco cigarette smokers exhibit deficits in response inhibition and sustained attention

BACKGROUND Initiation of cigarette smoking during adolescence coincides with structural and cognitive neuromaturation. Thus, early onset smokers (EOS; initiated <16 years old) may be at unique risk of altered development of executive function relative to late onset smokers (LOS; initiated >16 years old). This study quantified the effects of age of smoking onset on response impulsivity and inhibitory control using a novel smoking Go/NoGo task (Luijten et al., 2011). METHODS Nicotine deprived adult EOS (n = 10) and LOS (n = 10) and adult healthy non-smokers (HNS; n = 10) were shown smoking-related and neutral images with either a blue (Go) or yellow (NoGo) frame. Participants were instructed to respond to blue-framed Go trials quickly and accurately, and withhold responding for yellow-framed NoGo trials. RESULTS EOS made more Go response accuracy errors (p ≤ 0.02) and failed more frequently to inhibit responses to NoGo trials (p < 0.02) than LOS and HNS. EOS also made more errors in inhibiting responses to smoking-related (p ≤ 0.02) and neutral (p ≤ 0.02) NoGo trials. EOS reported greater baseline craving for cigarette smoking than LOS (p < 0.04), and craving was significantly associated with greater omission errors (p ≤ 0.04). CONCLUSIONS EOS exhibited greater difficulty than LOS in responding accurately to Go stimuli and withholding responses to both smoking and neutral NoGo stimuli, indicating greater response impulsivity, poor attention, and deficits in response inhibition. These findings suggest that EO smoking, in particular, contributes to diminished task-related attention and inhibitory control behaviors in adulthood and provide support for the tobacco-induced neurotoxicity of adolescent cognitive development (TINACD) theory (DeBry and Tiffany, 2008).