Neurobehavioral Systems Research Articles

Neurobehavioral Deficits After Subarachnoid Hemorrhage in Mice: Sensitivity Analysis and Development of a New Composite Score.

BackgroundBecause of the failure of numerous clinical trials, various recommendations have been made to improve the usefulness of preclinical studies. Specifically, the STAIR (Stroke Therapy Academic Industry Roundtable) recommendations highlighted functional outcome as a critical measure. Recent reviews of experimental subarachnoid hemorrhage (SAH) studies have brought to light the numerous neurobehavioral scoring systems that are used in preclinical SAH studies. To gain insight into the utility of these scoring systems, as well as to identify a scoring system that best captures the deficits caused by SAH in mice, we designed the current study.Methods and ResultsAdult male C57BL/6J mice were used. One cohort of mice was randomly allocated to either sham or SAH and had functional testing performed on days 1 to 3 post‐SAH using the modified Bederson Score, Katz Score, Garcia Neuroscore, and Parra Neuroscore, as well as 21 individual subtests. A new composite neuroscore was developed using the 8 most diagnostically accurate subtests. To validate the use of the developed composite neuroscore, another cohort of mice was randomly assigned to either the sham or SAH group and neurobehavior was evaluated on days 1 to 3, 5, and 7 after injury. Receiver operating characteristic curves were used to analyze the diagnostic accuracy of each scoring system, as well as the subtests. Of the 4 published scoring systems, the Parra Neuroscore was diagnostically accurate for SAH injury in mice versus the modified Bederson and Katz Scores, but not the Garcia Neuroscore. However, the newly developed composite neuroscore was found to be statistically more diagnostically accurate than even the Parra Neuroscore.ConclusionsThe findings of this study promote use of the newly developed composite neuroscore for experimental SAH studies in mice.

Autonomic regulation of preterm infants is enhanced by Family Nurture Intervention.

Preterm infants have maturational delays in several neurobehavioral systems. This study assesses the impact of the Family Nurture Intervention (FNI) in the neonatal intensive care unit (NICU) on the maturation of autonomic regulation of preterm infants. Preterm infants born at 26-34weeks postmenstrual age (PMA) were assigned to groups receiving either standard care (SC) or SC plus FNI, using a randomized controlled trial design. At two collection time points, approximately 35weeks and 41weeks PMA, electrocardiograms (ECG) were monitored for approximately 1hour during sleep. Heart rate and respiratory sinus arrhythmia (RSA) were quantified from the ECG. Across the two time points, the FNI group exhibited greater increases in RSA (Cohen's d=0.35) and slope between RSA and heart rate, as a measure of vagal efficiency (Cohen's d=0.62). These results document that FNI resulted in enhanced autonomic regulation consistent with greater maturation of cardiac function. These and previous findings strongly suggest that facilitating early nurturing interactions and emotional connection between preterm infants and their mothers is a practicable and effective means of optimizing postnatal development in preterm infants. Interpretation of these autonomic function results also enriches our understanding of the potential long-term beneficial outcomes of FNI by drawing upon polyvagal theory, which explains how autonomic state provides a neurophysiological platform for optimal co-regulation between infant and caregiver, and by drawing upon calming cycle theory, which provides a model for understanding how repeated mother/infant calming interactions positively condition autonomic state and reinforce approach, prosocial behaviors.

Inward versus reward: white matter pathways in extraversion.

The trait of extraversion is one of the longest-standing domains that captures the social dimension of personality and can potentially explain the covariation of a wide variety of behaviors. To date, there is a growing recognition that human behavior should be specified not only through the psychological mechanisms underlying each trait but also through their underlying neurobehavioral systems. While imaging studies have revealed important initial insights into the structural and functional neural correlates of extraversion, current knowledge about the relationships between extraversion and brain structures is still rather limited, especially with regard to the relationship between extraversion and white matter (WM). In this study, we aimed to investigate WM microstructure in extraversion in greater depth. Thirty-five healthy volunteers (21 women; mean age 35) underwent magnetic resonance imaging, as a part of a larger project aimed at investigating the longitudinal effect of motor training. WM integrity was assessed using the diffusion tensor imaging technique combining multiple diffusion tensor measures. Extraversion was assessed by the Eysenck Personality Questionnaire-Revised. Voxelwise correlation analyses between fractional anisotropy, axial diffusivities, and radial diffusivities maps and extraversion score showed decreased connectivity in the right inferior fronto-occipital fasciculus and forceps major among individuals who had high extraversion ratings. In conclusion, individual differences in extraversion may reflect differential organization of the WM tracts connecting frontal cortex, temporal, and occipital areas, which are related to socioemotional and control functions.

Intra-Individual Variability in Vagal Control Is Associated With Response Inhibition Under Stress.

Dynamic intra-individual variability (IIV) in cardiac vagal control across multiple situations is believed to contribute to adaptive cognition under stress; however, a dearth of research has empirically tested this notion. To this end, we examined 25 U.S. Army Soldiers (all male, mean age = 30.73, standard deviation (SD) = 7.71) whose high-frequency heart rate variability (HF-HRV) was measured during a resting baseline and during three conditions of a shooting task (training, low stress, high stress). Response inhibition was measured as the correct rejection (CR) of friendly targets during the low and high stress conditions. We tested the association between the SD of HF-HRV across all four task conditions (IIV in vagal control) and changes in response inhibition between low and high stress. Greater differences in vagal control between conditions (larger IIV) were associated with higher tonic vagal control during rest, and stronger stress-related decreases in response inhibition. These results suggest that flexibility in vagal control is supported by tonic vagal control, but this flexibility also uniquely relates to adaptive cognition under stress. Findings are consistent with neurobehavioral and dynamical systems theories of vagal function.

Environmental Enrichment During Adolescence Acts as a Protective and Therapeutic Tool for Ethanol Binge-Drinking, Anxiety-Like, Novelty Seeking and Compulsive-Like Behaviors in C57BL/6J Mice During Adulthood.

Repetitive drug/ethanol (EtOH) binge-like consumption during pre-addictive stages favors a transition to addiction in vulnerable organisms. Experimental evidence points to the therapeutic and preventive effects of environmental enrichment (EE) on drug and EtOH addiction; however, little is known regarding EE modulation of binge-like consumption in non-dependent organisms. Here, we explore the impact of early EE on binge-like EtOH consumption: (1) we test whether early EE exposure prevents binge-like EtOH intake (20% v/v) in adult mice under an intermittent drinking in the dark (iDID) schedule; (2) we evaluate the therapeutic effects of EE housing conditions on binge-like EtOH consumption in adult animals; and (3) we compare novelty-seeking and compulsive-like behaviors, and anxiety-like behavior, as measured by the Hole Board (HB) and Elevated Plus Maze (EPM) tests, respectively, in adult EE/standard environment (SE) animals. Adolescent (postnatal day 28; PND28) mice were randomly allocated to two housing conditions (4 animals/cage): EE or SE. At PND67 all the animals were exposed to a schedule of EtOH binge-like iDID. On PND92 half of the animals in each environmental condition (EE and SE) were randomly allocated to two subgroups in a crossover design, where environmental conditions were kept similar to those previously experienced or switched, finally leading to four experimental conditions: EE-EE, EE-SE, SE-SE, and SE-EE. EtOH binge-like consumption continued until PND140, when EPM and HB tests were finally conducted. The main observations were: (1) EE-reared mice showed lower EtOH binge-like intake than SE-reared mice during adulthood, which supports a protective role for EE. (2) when adult EtOH drinking SE-reared mice were switched to EE conditions, a reduction in EtOH binge-like consumption was observed, suggesting a therapeutic role for EE; however, losing EE during adulthood triggered a progressive increase in EtOH binge-like intake. Moreover, (3) EE-housed adult animals with long-term exposure to EtOH binge-drinking showed lower anxiety-like, compulsive-like, and novelty-seeking behaviors than SE-housed mice, irrespective of the specific housing conditions during adolescence. We discuss the primary impact of EE on anxiety-like neurobehavioral brain systems through which it secondarily modulates EtOH binge-like drinking.

Experts Search for Meds to Help Youth With DMDD

Experts Search for Meds to Help Youth With DMDD

EU to lower limit for bisphenol A migration

A draft European Commission regulation that lowers the amount of bisphenol A (BPA) allowed to migrate into or onto food from packaging materials is expected to be finalized in the coming months. Members of the European Parliament’s Environment, Public Health, & Food Safety Committee voted on Jan. 11 to reject a proposal to ban BPA in food packaging. The committee instead endorsed the Commission’s proposal to lower the migration limit from 0.6 mg of BPA per kg of food to 0.05 mg/kg. BPA is used to manufacture polycarbonate plastic and epoxy resins found in coatings that line food cans. Concerns about BPA’s estrogenic activity have prompted regulators around the world to evaluate the substance’s risks in materials that contact food. The Commission’s proposal cites “potential health effects of BPA on the mammary gland, reproductive, metabolic, neurobehavioral, and immune systems.” The draft regulation prohibits any BPA from migrating into infant formula

How Stuttering Develops: The Multifactorial Dynamic Pathways Theory.

We advanced a multifactorial, dynamic account of the complex, nonlinear interactions of motor, linguistic, and emotional factors contributing to the development of stuttering. Our purpose here is to update our account as the multifactorial dynamic pathways theory. We review evidence related to how stuttering develops, including genetic/epigenetic factors; motor, linguistic, and emotional features; and advances in neuroimaging studies. We update evidence for our earlier claim: Although stuttering ultimately reflects impairment in speech sensorimotor processes, its course over the life span is strongly conditioned by linguistic and emotional factors. Our current account places primary emphasis on the dynamic developmental context in which stuttering emerges and follows its course during the preschool years. Rapid changes in many neurobehavioral systems are ongoing, and critical interactions among these systems likely play a major role in determining persistence of or recovery from stuttering. Stuttering, or childhood onset fluency disorder (Diagnostic and Statistical Manual of Mental Disorders, 5th edition; American Psychiatric Association [APA], 2013), is a neurodevelopmental disorder that begins when neural networks supporting speech, language, and emotional functions are rapidly developing. The multifactorial dynamic pathways theory motivates experimental and clinical work to determine the specific factors that contribute to each child's pathway to the diagnosis of stuttering and those most likely to promote recovery.

Applying Melanopic Lux to Measure Biological Light Effects on Melatonin Suppression and Subjective Sleepiness

At the beginning of this century, a novel photopigment, melanopsin, was discovered in a sub-class of retinal ganglion cells and its action spectrum was described. Shortly after, it became evident that melanopsin is a major contributor to non-visual eye-mediated effects of light on e.g. the circadian, neuroendocrine and neurobehavioral systems. First applied studies pointed out that these non-visual effects of light are relevant for wellbeing, performance and general health. A standardized measurement metric for these nonvisual effects does not exist, but would ease application. Such a metric termed as 'melanopic lux' has been recently introduced and was shown to be superior to describe non-visual effects in animal studies compared to standard metrics. We aimed at showing some validity of melanopic lux in humans using a seminaturalistic setting. Therefore, we analyzed the impact of different lighting conditions on melatonin suppression and subjective sleepiness by calculating effective illuminance based on single photopigment sensitivities. We retrospectively analyzed data from our laboratory, where young participants were exposed to a total of 19 different polychromatic lighting conditions, for 30 minutes in the evening, one hour prior to habitual bedtime. Saliva samples for melatonin concentration measures and subjective sleepiness were regularly assessed. The photopic illuminance of all lighting conditions ranged from 3 to 604 lx. Stepwise for- and backward regression analyses showed that melanopic lux was the best predictor for changes in melatonin concentrations (but not subjective sleepiness); R²=0.16 (p<0.05). In addition, we found a significant dose-response relationship between melanopic lux and changes in melatonin concentrations for 18 different lighting conditions (adjusted R²=0.52; p=0.004), similarly to what was previously reported for photopic lux. Our results indicate some new relevance for the application of melanopic lux as an additional metric to predict non-visual light effects of electrical light sources for nursing homes, work places, and homes.

Personality and placebo analgesia during cold stimulation in women: A Low-Resolution Brain Electromagnetic Tomography (LORETA) analysis of startle ERPs

We applied exact low-resolution brain electromagnetic tomography (eLORETA) method to auditory startle event-related potentials (ERPs) during cold pain (cold-cup-test: CCT). ERPs and startle data were obtained from a published dataset wherein auditory startle stimuli were used as probes of pain processing (De Pascalis & Scacchia, 2016). We wanted to identify (1) sources of cortical current density changes associated with pain/distress reductions to placebo analgesia (PA) treatment, and (2) sources of activity changes that are predictors of the behavioural inhibition system (BIS) and fight/flight/freeze system (FFFS) of the revised Reinforcement Sensitivity Theory (rRST). We administered three treatments: Baseline, CCT-alone (Pain), and CCT plus sham cream (Placebo). PA, as compared to Pain treatment, was effective in pain and distress reduction, and produced a significant current density reduction within right primary somatosensory cortex (S1) and left middle frontal gyrus (MFG). In addition, current density change in the right S1 was a positive predictor of subjective pain and distress reduction, although distress reduction was also associated with decreased activity in the left MFG. We failed to identify regional sources of placebo-related current density changes as predictors of the BIS and FFFS with the exception of current density changes within left MFG that was positively correlated with BIS and a significant predictor of this trait. Findings appear consistent with rRST predictions suggesting BIS and FFFS as separate, but interacting neurobehavioural systems.

Is "Learning" episodic memory? Distinct cognitive and neuroanatomic correlates of immediate recall during learning trials in neurologically normal aging and neurodegenerative cohorts.

Although commonly interpreted as a marker of episodic memory during neuropsychological exams, relatively little is known regarding the neurobehavior of "total learning" immediate recall scores. Medial temporal lobes are clearly associated with delayed recall performances, yet immediate recall may necessitate networks beyond traditional episodic memory. We aimed to operationalize cognitive and neuroanatomic correlates of total immediate recall in several aging syndromes. Demographically-matched neurologically normal adults (n=91), individuals with Alzheimer's disease (n=566), logopenic variant primary progressive aphasia (PPA) (n=34), behavioral variant frontotemporal dementia (n=97), semantic variant PPA (n=71), or nonfluent/agrammatic variant PPA (n=39) completed a neurocognitive battery, including the CVLT-Short Form trials 1-4 Total Immediate Recall; a majority subset also completed a brain MRI. Regressions covaried for age and sex, and MMSE in cognitive and total intracranial volume in neuroanatomic models. Neurologically normal adults demonstrated a heterogeneous pattern of cognitive associations with total immediate recall (executive, speed, delayed recall), such that no singular cognitive or neuroanatomic correlate uniquely predicted performance. Within the clinical cohorts, there were syndrome-specific cognitive and neural associations with total immediate recall; e.g., semantic processing was the strongest cognitive correlate in svPPA (partial r=0.41), while frontal volumes was the only meaningful neural correlate in bvFTD (partial r=0.20). Medial temporal lobes were not independently associated with total immediate recall in any group (ps>0.05). Multiple neurobehavioral systems are associated with "total learning" immediate recall scores that importantly differ across distinct clinical syndromes. Conventional memory networks may not be sufficient or even importantly contribute to total immediate recall in many syndromes. Interpreting learning scores as equivalent to episodic memory may be erroneous.

Personality and Augmenting/Reducing (A/R) in auditory event-related potentials (ERPs) during emotional visual stimulation

An auditory augmenting/reducing ERP paradigm recorded for 5 intensity tones with emotional visual stimulation was used, for the first time, to test predictions derived from the revised Reinforcement Sensitivity Theory (rRST) of personality with respect to two major factors: behavioral inhibition system (BIS), fight/flight/freeze system (FFFS). Higher BIS and FFFS scores were negatively correlated with N1/P2 slopes at central sites (C3, Cz, C4). Conditional process analysis revealed that the BIS was a mediator of the association between the N1/P2 slope and the FFFS scores. An analysis of covariance showed that lower BIS scorers exhibited larger N1/P2 amplitudes across all tone intensities while watching negative, positive and neutral pictures. Additionally, lower FFFS scorers compared to higher FFFS scorers disclosed larger N1/P2 amplitudes to the highest tone intensities and these differences were even more pronounced while watching positive emotional pictures. Findings were explained assuming the operation of two different, but related processes: transmarginal inhibition for the BIS; the attention/emotional gating mechanism regulating cortical sensory input for the FFFS trait. These findings appear consistent with predictions derived from the rRST, which traced fear and anxiety to separate but interacting neurobehavioural systems.

Childhood Stuttering: Where Are We and Where Are We Going?

Remarkable progress has been made over the past two decades in expanding our understanding of the behavioral, peripheral physiologic, and central neurophysiologic bases of stuttering in early childhood. It is clear that stuttering is a neurodevelopmental disorder characterized by atypical development of speech motor planning and execution networks. The speech motor system must interact in complex ways with neural systems mediating language and other cognitive and emotional processes. During the time when stuttering typically appears and follows its path to either recovery or persistence, all of these neurobehavioral systems are undergoing rapid and dramatic developmental changes. We summarize our current understanding of the various developmental trajectories relevant for the understanding of stuttering in early childhood. We also present theoretical and experimental approaches that we believe will be optimal for even more rapid progress toward developing better and more targeted treatment for stuttering in the preschool children who are more likely to persist in stuttering.

Beyond the Medial Regions of Prefrontal Cortex in the Regulation of Fear and Anxiety.

Fear and anxiety are adaptive responses but if left unregulated, or inappropriately regulated, they become biologically and socially maladaptive. Dysregulated emotions are manifest in a wide variety of psychiatric and neurological conditions but the external expression gives little indication of the underlying causes, which are inevitably multi-determined. To go beyond the overt phenotype and begin to understand the causal mechanisms leading to conditions characterized by anxiety and disorders of mood, it is necessary to identify the base psychological processes that have become dysregulated, and map them on to their associated neural substrates. So far, attention has been focused primarily on the medial regions of prefrontal cortex (PFC) and in particular their contribution to the expression and extinction of conditioned fear. However, functional neuroimaging studies have shown that the sphere of influence within the PFC is not restricted to its medial regions, but extends into dorsal, ventrolateral (vlPFC) and orbitofrontal (OFC) regions too; although the causal role of these other areas in the regulation of fear and anxiety remains to be determined and in the case of the OFC, existing findings are conflicting. Here, we review the evidence for the contribution of these other regions in negative emotion regulation in rodents and old world and new world monkeys. We consider a variety of different contexts, including conditioned and innate fear, learned and unlearned anxiety and cost-benefit decision-making, and a range of physiological and behavioral measures of emotion. It is proposed that both the OFC and vlPFC contribute to emotion regulation via their involvement, respectively, in the prediction of future outcomes and higher-order attentional control. The fractionation of these neurocognitive and neurobehavioral systems that regulate fear and anxiety opens up new opportunities for diagnostic stratification and personalized treatment strategies.

Metacognitive Control of Categorial Neurobehavioral Decision Systems.

The competing neuro-behavioral decision systems (CNDS) model proposes that the degree to which an individual discounts the future is a function of the relative hyperactivity of an impulsive system based on the limbic and paralimbic brain regions and the relative hypoactivity of an executive system based in prefrontal cortex (PFC). The model depicts the relationship between these categorial systems in terms of the antipodal neurophysiological, behavioral, and decision (cognitive) functions that engender normal and addictive responding. However, a case may be made for construing several components of the impulsive and executive systems depicted in the model as categories (elements) of additional systems that are concerned with the metacognitive control of behavior. Hence, this paper proposes a category-based structure for understanding the effects on behavior of CNDS, which includes not only the impulsive and executive systems of the basic model but a superordinate level of reflective or rational decision-making. Following recent developments in the modeling of cognitive control which contrasts Type 1 (rapid, autonomous, parallel) processing with Type 2 (slower, computationally demanding, sequential) processing, the proposed model incorporates an arena in which the potentially conflicting imperatives of impulsive and executive systems are examined and from which a more appropriate behavioral response than impulsive choice emerges. This configuration suggests a forum in which the interaction of picoeconomic interests, which provide a cognitive dimension for CNDS, can be conceptualized. This proposition is examined in light of the resolution of conflict by means of bundling.

Competing neurobehavioral decision systems theory of cocaine addiction: From mechanisms to therapeutic opportunities.

Cocaine dependence is a difficult-to-treat, chronically relapsing disorder. Multiple scientific disciplines provide distinct perspectives on this disorder; however, connections between disciplines are rare. The competing neurobehavioral decision systems (CNDS) theory posits that choice results from the interaction between two decision systems (impulsive and executive) and that regulatory imbalance between systems can induce pathology, including addiction. Using this view, we integrate a diverse set of observations on cocaine dependence, including bias for immediacy, neural activity and structure, developmental time course, behavioral comorbidities, and the relationship between cocaine dependence and socioeconomic status. From the CNDS perspective, we discuss established and emerging behavioral, pharmacological, and neurological treatments and identify possible targets for future treatments. The ability of the CNDS theory to integrate diverse findings highlights its utility for understanding cocaine dependence and supports that dysregulation between the decision systems contributes to addiction.

Isolating the incentive salience of reward-associated stimuli: value, choice, and persistence.

Sign- and goal-tracking are differentially associated with drug abuse-related behavior. Recently, it has been hypothesized that sign- and goal-tracking behavior are mediated by different neurobehavioral valuation systems, including differential incentive salience attribution. Herein, we used different conditioned stimuli to preferentially elicit different response types to study the different incentive valuation characteristics of stimuli associated with sign- and goal-tracking within individuals. The results demonstrate that all stimuli used were equally effective conditioned stimuli; however, only a lever stimulus associated with sign-tracking behavior served as a robust conditioned reinforcer and was preferred over a tone associated with goal-tracking. Moreover, the incentive value attributed to the lever stimulus was capable of promoting suboptimal choice, leading to a significant reduction in reinforcers (food) earned. Furthermore, sign-tracking to a lever was more persistent than goal-tracking to a tone under omission and extinction contingencies. Finally, a conditional discrimination procedure demonstrated that sign-tracking to a lever and goal-tracking to a tone were dependent on learned stimulus–reinforcer relations. Collectively, these results suggest that the different neurobehavioral valuation processes proposed to govern sign- and goal-tracking behavior are independent but parallel processes within individuals. Examining these systems within individuals will provide a better understanding of how one system comes to dominate stimulus–reward learning, thus leading to the differential role these systems play in abuse-related behavior.

Neurodevelopment and phenotype-modulating functions of S100B protein: A pilot study

The importance of certain neurotrophic proteins found in maternal blood and milk for breastfed infants has remained ambiguous. This study was conducted to present evidence of the impact of an induced deficit of active S100B protein on neonate development. Newborn mice from two groups of mothers, immunized or sham-immunized against S100B, were subjected to various behavioral tests, and the development of their morphological characteristics was recorded from birth until weaning. Morphological problems, including weight gain and fur coating, a delay in the maturation of neurobehavioral systems and a deficit in neuromotor functions, including visual abilities, somato-sensory and posture reactions, muscular strength, locomotion, and fear/orienting processes, were observed in pups of immunized mothers. The S100B protein of external or internal origin in infants may be considered to be a specific factor that determines neuro- and morphological development and a risk-avoidance (‘homeward-bent’ or fearful) phenotype. The suppression of activity of the S100B protein results in a slower neonatal development and the formation of a risk-tolerant (fearless) phenotype of the offspring. This study thus considers the mechanism of neuroplastic regulation on the extent of sensation-seeking or risk-taking (homeless-like or fearless) and sensation- or risk-avoidance (home-bound or fearful) features in individual phenotypes.

Moods as ups and downs of the motivation pendulum: revisiting reinforcement sensitivity theory (RST) in bipolar disorder.

Motivation is a key neurobehavioral concept underlying adaptive responses to environmental incentives and threats. As such, dysregulation of motivational processes may be critical in the formation of abnormal behavioral patterns/tendencies. According to the long standing model of the Reinforcement Sensitivity Theory (RST), motivation behaviors are driven by three neurobehavioral systems mediating the sensitivity to punishment, reward or goal-conflict. Corresponding to current neurobehavioral theories in psychiatry, this theory links abnormal motivational drives to abnormal behavior; viewing depression and mania as two abnormal extremes of reward driven processes leading to either under or over approach tendencies, respectively. We revisit the RST framework in the context of bipolar disorder (BD) and challenge this concept by suggesting that dysregulated interactions of both punishment and reward related processes better account for the psychological and neural abnormalities observed in BD. We further present an integrative model positing that the three parallel motivation systems currently proposed by the RST model, can be viewed as subsystems in a large-scale neurobehavioral network of motivational decision making.

Competing neurobehavioral decision systems and the neuroeconomics of craving in opioid addiction

Competing neurobehavioral decision systems and the neuroeconomics of craving in opioid addiction Michael J Sofis,1 David P Jarmolowicz,1 Laura E Martin2 1University of Kansas, 2University of Kansas Medical Center, Lawrence, KS, USA Abstract: Craving is typically thought of as a classically conditioned response characterized by an elevated mesolimbic dopamine response to drug-related stimuli. Although this definition has spurred considerable research, the clinical impact of the research conducted has been less robust. The current review takes a more contemporary approach by conceptualizing craving as the breakdown of executive function and relative strengthening of the limbic system, occurring in the presence of conditioned cues, leading to a maladaptive craving response (ie, an increased likelihood of drug consumption). Working from this framework, the present review focuses on four issues in drug craving research: pivotal findings and limitations of cue-reactivity and neurocognitive tasks; two main processes of craving that include self-control and reward-based explanations; integration of neuroeconomic approaches to craving; and the theoretical implications and future directions of drug craving research. Keywords: craving, competing decision systems, executive function, loss of control, substance abuse&nbsp;