Dorsal medial prefrontal cortex (MPFC) circuitry in rodent models of cocaine use: implications for drug addiction therapies.

Although the importance of the medial prefrontal cortex (MPFC) in cocaine addiction is well established, its precise contribution to cocaine seeking, taking and relapse remains incompletely understood. In particular, across two different models of cocaine self-administration, pharmacological or optogenetic activation of the dorsal MPFC has been reported to sometimes promote and sometimes inhibit cocaine seeking. We highlight important methodological differences between the two experimental paradigms and propose a framework to potentially reconcile the apparent discrepancy. We also draw parallels between these pre-clinical models of cocaine self-administration and human neuro-imaging studies in cocaine users, and argue that both lines of evidence point to dynamic interactions between cue-reactivity processes and control processes within the dorsal MPFC circuitry. From a translational perspective, these findings underscore the importance of interventions and therapeutics targeting not just a brain region, but a specific computational process within that brain region, and may have implications for the design and implementation of more effective treatments for human cocaine addiction.

Factors modulating neural reactivity to drug cues in addiction: a survey of human neuroimaging studies.

Human neuroimaging studies suggest that neural cue reactivity is strongly associated with indices of drug use, including addiction severity and treatment success. However, little is known about factors that modulate cue reactivity. The goal of this review, in which we survey published fMRI and PET studies on drug cue reactivity in cocaine, alcohol, and tobacco cigarette users, is to highlight major factors that modulate brain reactivity to drug cues. First, we describe cue reactivity paradigms used in neuroimaging research and outline the brain circuits that underlie cue reactivity. We then discuss major factors that have been shown to modulate cue reactivity and review specific evidence as well as outstanding questions related to each factor. Building on previous model-building reviews on the topic, we then outline a simplified model that includes the key modulatory factors and a tentative ranking of their relative impact. We conclude with a discussion of outstanding challenges and future research directions, which can inform future neuroimaging studies as well as the design of treatment and prevention programs.

Dual role of nicotine in addiction and cognition: a review of neuroimaging studies in humans.

Substantial evidence demonstrates both nicotine's addiction liability and its cognition-enhancing effects. However, the neurobiological mechanisms underlying nicotine's impact on brain function and behavior remain incompletely understood. Elucidation of these mechanisms is of high clinical importance and may lead to improved therapeutics for smoking cessation as well as for a number of cognitive disorders such as schizophrenia. Neuroimaging techniques such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and functional magnetic resonance imaging (fMRI), which make it possible to study the actions of nicotine in the human brain in vivo, play an increasingly important role in identifying these dual mechanisms of action. In this review, we summarize the current state of knowledge and discuss outstanding questions and future directions in human neuroimaging research on nicotine and tobacco. This research spans from receptor-level PET and SPECT studies demonstrating nicotine occupancy at nicotinic acetylcholine receptors (nAChRs) and upregulation of nAChRs induced by chronic smoking; through nicotine's interactions with the mesocorticolimbic dopamine system believed to mediate nicotine's reinforcing effects leading to dependence; to functional activity and connectivity fMRI studies documenting nicotine's complex behavioral and cognitive effects manifest by its actions on large-scale brain networks engaged both during task performance and at rest. This article is part of the Special Issue Section entitled 'Neuroimaging in Neuropharmacology'.

Task difficulty modulates the impact of emotional stimuli on neural response in cognitive-control regions.

Both heightened reactivity to emotional stimuli and impaired cognitive control are key aspects of depression, anxiety, and addiction. But the impact of emotion on cognitive-control processes, and the factors that modulate this impact, are still not well understood. We examined the effects of threat and reward distracters on the neural correlates of cognitive control using functional MRI (fMRI) and the Multi-Source Interference Task (MSIT). Behaviorally, subjects were slower and less accurate on the more demanding incongruent trials compared to the easier congruent trials. In addition, both threat and reward distracters significantly impaired the speed of responding on incongruent trials relative to the no-distracter condition. At the neural level, we used the incongruent - congruent contrast to functionally define four cognitive-control regions of interest (ROIs): anterior cingulate cortex (ACC), left and right inferior frontal gyrus (IFG)/insula, and right dorsolateral prefrontal cortex (DLPFC). A repeated-measures analysis of variance on the extracted contrast values in these ROIs indicated a significant interaction of stimulus salience and task difficulty on the neural response in cognitive-control regions. Specifically, threat distracters significantly decreased the response in cognitive-control regions on incongruent trials, whereas they significantly increased that response on congruent trials, relative to the no-distracter condition. Exploratory analyses of the amygdala response showed a similar interaction of stimulus salience and task difficulty: threat distracters significantly decreased the amygdala response only on incongruent trials. Overall, our results suggest that the impact of emotional distracters on the neural response in cognitive-control regions as well as in the amygdala is modulated by task difficulty, and add to our understanding of the factors that determine whether emotion enhances or impairs cognition.

Impulsivity and inhibitory control deficits are associated with unhealthy eating in young adults.

Heightened impulsivity and inefficient inhibitory control are increasingly recognized as risk factors for unhealthy eating and obesity but the underlying processes are not fully understood. We used structural equation modeling to investigate the relationships between impulsivity, inhibitory control, eating behavior, and body mass index (BMI) in 210 undergraduates who ranged from underweight to obese. We demonstrate that impulsivity and inhibitory control deficits are positively associated with several facets of unhealthy eating, including overeating in response to external food cues and in response to negative emotional states, and making food choices based on taste preferences without consideration of health value. We further show that such unhealthy eating is, for the most part, associated with increased BMI, with the exception of Restraint Eating, which is negatively associated with BMI. These results add to our understanding of the impact of individual differences in impulsivity and inhibitory control on key aspects of unhealthy eating and may have implications for the treatment and prevention of obesity.

An imaging genetics approach to understanding social influence.

Normative social influences shape nearly every aspect of our lives, yet the biological processes mediating the impact of these social influences on behavior remain incompletely understood. In this Hypothesis, we outline a theoretical framework and an integrative research approach to the study of social influences on the brain and genetic moderators of such effects. First, we review neuroimaging evidence linking social influence and conformity to the brain's reward system. We next review neuroimaging evidence linking social punishment (exclusion) to brain systems involved in the experience of pain, as well as evidence linking exclusion to conformity. We suggest that genetic variants that increase sensitivity to social cues may predispose individuals to be more sensitive to either social rewards or punishments (or potentially both), which in turn increases conformity and susceptibility to normative social influences more broadly. To this end, we review evidence for genetic moderators of neurochemical responses in the brain, and suggest ways in which genes and pharmacology may modulate sensitivity to social influences. We conclude by proposing an integrative imaging genetics approach to the study of brain mediators and genetic modulators of a variety of social influences on human attitudes, beliefs, and actions.

Influence of threat and serotonin transporter genotype on interference effects.

Emotion-cognition interactions are critical in goal-directed behavior and may be disrupted in psychopathology. Growing evidence also suggests that emotion-cognition interactions are modulated by genetic variation, including genetic variation in the serotonin system. The goal of the current study was to examine the impact of threat-related distracters and serotonin transporter promoter polymorphism (5-HTTLPR/rs25531) on cognitive task performance in healthy females. Using a novel threat-distracter version of the Multi-Source Interference Task specifically designed to probe emotion-cognition interactions, we demonstrate a robust and temporally dynamic modulation of cognitive interference effects by threat-related distracters relative to other distracter types and relative to no-distracter condition. We further show that threat-related distracters have dissociable and opposite effects on cognitive task performance in easy and difficult task conditions, operationalized as the level of response interference that has to be surmounted to produce a correct response. Finally, we present evidence that the 5-HTTLPR/rs25531 genotype in females modulates susceptibility to cognitive interference in a global fashion, across all distracter conditions, and irrespective of the emotional salience of distracters, rather than specifically in the presence of threat-related distracters. Taken together, these results add to our understanding of the processes through which threat-related distracters affect cognitive processing, and have implications for our understanding of disorders in which threat signals have a detrimental effect on cognition, including depression and anxiety disorders.

Serotonin transporter gene, stress and raphe-raphe interactions: a molecular mechanism of depression.

Reports of gene-environment interactions (GxE) between the serotonin transporter gene and stress on risk of depression have generated both excitement and controversy. The controversy persists in part because a mechanistic account of this GxE on serotonergic neurotransmission and risk of depression has been lacking. In this Opinion, we draw on recent discoveries in the functional neuroanatomy of the serotonergic dorsal raphe nucleus (DR) to propose such a mechanistic account. We argue that genetically produced variability in serotonin reuptake during stressor-induced raphe-raphe interactions alters the balance in the amygdala-ventromedial prefrontal cortex (VMPFC)-DR circuitry underlying stressor reactivity and emotion regulation. In particular, the recently characterized stressor-responsive serotonergic interneurons originating from the dorsolateral DR may hold a key to unlocking the GxE mechanism of depression.

Amygdala response to smoking-cessation messages mediates the effects of serotonin transporter gene variation on quitting.

The amygdala is critically involved in detecting emotionally salient stimuli and in enhancing memory for emotional information. Growing evidence also suggests that the amygdala plays a crucial role in addiction, perhaps by strengthening associations between emotionally-charged drug cues and drug-seeking behavior. In the current study, by integrating functional MRI (fMRI), genetics, and outcome data from a large group of smokers who completed a smoking-cessation intervention and attempted to quit, we show that the amygdala also plays a role in quitting. Specifically, we demonstrate that the amygdala response to smoking-cessation messages in smokers trying to quit is a predictor of their post-intervention quitting outcome. We further show that the amygdala response is modulated by genetic variation in the serotonin transporter and mediates the impact of this genetic variation on quitting. These results point to a gene-brain-behavior pathway relevant to smoking cessation, and add to our understanding of the role of the amygdala in nicotine addiction.

Self-related neural response to tailored smoking-cessation messages predicts quitting.

Tailored health interventions can be more effective in eliciting positive behavior change than generic interventions, but the underlying neural mechanisms are not yet understood. Here, 91 smokers participated in a functional magnetic resonance imaging session and a tailored smoking-cessation program. We found that increases in activation in self-related processing regions, particularly dorsomedial prefrontal cortex, to tailored messages predicted quitting during a 4-month follow-up.