Effect of Robotic Exoskeleton Motion Constraints on Upper Limb Muscle Synergies: A Case Study.

Evidence exists that changes in composition, timing, and number of muscle synergies can be correlated to functional changes resulting from neurological injury. These changes can also serve as an indicator of level of motor impairment. As such, synergy analysis can be used as an assessment tool for robotic rehabilitation. However, it is unclear whether using a rehabilitation robot to isolate limb movements during training affects the subject's muscle synergies, which would affect synergy-based assessments. In this case study, electromyographic (EMG) data were collected to analyze muscle synergies generated during single degree-of-freedom (DoF) elbow and wrist movements performed by a single healthy subject in a four DoF robotic exoskeleton. For each trial, the subject was instructed to move a single DoF from a neutral position out to a target and back while the remaining DoFs were held in a neutral position by either the robot (constrained) or the subject (unconstrained). Four factorization methods were used to calculate muscle synergies for both types of trials: concatenation, averaging, single trials, and bootstrapping. The number of synergies was chosen to achieve 90% global variability accounted for. Our preliminary results indicate that muscle synergy composition and timing were highly similar for constrained and unconstrained trials, though some differences between the four factorization methods existed. These differences could be explained by higher trial-to-trial EMG variability for the unconstrained trials. These results suggest that using a robotic exoskeleton to constrain limb movements during robotic training may not alter a subject's muscle synergies, at least for healthy subjects.

Examining Social Cognition with Embodied Robots: Does Prior Experience with a Robot Impact Feedback-associated Learning in a Gambling Task?

Social agents rely on the ability to use feedback to learn and modify their behavior. The extent to which this happens in social contexts depends on motivational, cognitive and/or affective parameters. For instance, feedback-associated learning occurs at different rates when the outcome of an action (e.g., winning or losing in a gambling task) affects oneself ("Self") versus another human ("Other"). Here, we examine whether similar context effects on feedback-associated learning can also be observed when the "other" is a social robot (here: Cozmo). We additionally examine whether a "hybrid" version of the gambling paradigm, where participants are free to engage in a dynamic interaction with a robot, then move to a controlled screen-based experiment can be used to examine social cognition in human-robot interaction. This hybrid method is an alternative to current designs where researchers examine the effect of the interaction on social cognition during the interaction with the robot. For that purpose, three groups of participants (n total = 60) interacted with Cozmo over different time periods (no interaction vs. a single 20 minute interaction in the lab vs. daily 20 minute interactions over five consecutive days at home) before performing the gambling task in the lab. The results indicate that prior interactions impact the degree to which participants benefit from feedback during the gambling task, with overall worse learning immediately after short-term interactions with the robot and better learning in the "Self" versus "Other" condition after repeated interactions with the robot. These results indicate that "hybrid" paradigms are a suitable option to investigate social cognition in human-robot interaction when a fully dynamic implementation (i.e., interaction and measurement dynamic) is not feasible.

A win-win situation: Does familiarity with a social robot modulate feedback monitoring and learning?

Social species rely on the ability to modulate feedback-monitoring in social contexts to adjust one's actions and obtain desired outcomes. When being awarded positive outcomes during a gambling task, feedback-monitoring is attenuated when strangers are rewarded, as less value is assigned to the awarded outcome. This difference in feedback-monitoring can be indexed by an event-related potential (ERP) component known as the Reward Positivity (RewP), whose amplitude is enhanced when receiving positive feedback. While the degree of familiarity influences the RewP, little is known about how the RewP and reinforcement learning are affected when gambling on behalf of familiar versus nonfamiliar agents, such as robots. This question becomes increasingly important given that robots may be used as teachers and/or social companions in the near future, with whom children and adults will interact with for short or long periods of time. In the present study, we examined whether feedback-monitoring when gambling on behalf of oneself compared with a robot is impacted by whether participants have familiarized themselves with the robot before the task. We expected enhanced RewP amplitude for self versus other for those who did not familiarize with the robot and that self-other differences in the RewP would be attenuated for those who familiarized with the robot. Instead, we observed that the RewP was larger when familiarization with the robot occurred, which corresponded to overall worse learning outcomes. We additionally observed an enhanced P3 effect for the high-familiarity condition, which suggests an increased motivation to reward. These findings suggest that familiarization with robots may cause a positive motivational effect, which positively affects RewP amplitudes, but interferes with learning.

The SE-AssessWrist for robot-aided assessment of wrist stiffness and range of motion: Development and experimental validation.

INTRODUCTION: Physical human-robot interaction offers a compelling platform for assessing recovery from neurological injury; however, robots currently used for assessment have typically been designed for the requirements of rehabilitation, not assessment. In this work, we present the design, control, and experimental validation of the SE-AssessWrist, which extends the capabilities of prior robotic devices to include complete wrist range of motion assessment in addition to stiffness evaluation. METHODS: The SE-AssessWrist uses a Bowden cable-based transmission in conjunction with series elastic actuation to increase device range of motion while not sacrificing torque output. Experimental validation of robot-aided wrist range of motion and stiffness assessment was carried out with five able-bodied individuals. RESULTS: The SE-AssessWrist achieves the desired maximum wrist range of motion, while having sufficient position and zero force control performance for wrist biomechanical assessment. Measurements of two-degree-of-freedom wrist range of motion and stiffness envelopes revealed that the axis of greatest range of motion and least stiffness were oblique to the conventional anatomical axes, and approximately parallel to each other. CONCLUSIONS: Such an assessment could be beneficial in the clinic, where standard clinical measures of recovery after neurological injury are subjective, labor intensive, and graded on an ordinal scale.

Subthreshold error corrections predict adaptive post-error compensations.

Relatively little is known about the relation between subthreshold error corrections and post-error behavioral compensations. The present study utilized lateralized beta power, which has been shown to index response preparation, to examine subthreshold error corrections in a task known to produce response conflict, the Simon task. We found that even when an overt correction is not made, greater activation of the corrective response, indexed by beta suppression ipsilateral to the initial responding hand, predicted post-error speeding, and enhanced post-error accuracy at the single-trial level. This provides support for the notion that response conflict associated with errors can be adaptive, and suggests that subthreshold corrections should be taken into account to fully understand error-monitoring processes. Furthermore, we expand on previous findings that demonstrate that post-error slowing and post-error accuracy can be dissociated, as well as findings that suggest that frontal midline theta oscillations and the error-related negativity (ERN) are dissociable neurocognitive processes.

Contrasting time and frequency domains: ERN and induced theta oscillations differentially predict post-error behavior.

The present study investigated the neural dynamics of error processing in both the time and frequency domains, as well as associated behavioral phenomena, at the single-trial level. We used a technique that enabled us to separately investigate the evoked and induced aspects of the EEG signal (Cohen & Donner, 2013, Journal of Neurophysiology, 110[12], 2752-2763). We found that at the single-trial level, while the (evoked) error-related negativity (ERN) predicted only post-error slowing (PES)-and only when errors occurred on incongruent trials-induced frontal midline theta power served as a robust predictor of both PES and post-error accuracy (PEA) regardless of stimulus congruency. Mediation models of both electrophysiological indices demonstrated that although the relationship between theta and PEA was mediated by PES, there was not a relationship between the ERN and PEA. Our data suggest that although the ERN and frontal midline theta index functionally related underlying cognitive processes, they are not simply the same process manifested in different domains. In addition, our findings are consistent with the adaptive theory of post-error slowing, as PES was positively associated with post-error accuracy at the single-trial level. More generally, our study provides additional support for the inclusion of a time-frequency approach to better understand the role of medial frontal cortex in action monitoring.

A Myoelectric Control Interface for Upper-Limb Robotic Rehabilitation Following Spinal Cord Injury.

Spinal cord injury (SCI) is a widespread, life-altering injury leading to impairment of sensorimotor function that, while once thought to be permanent, is now being treated with the hope of one day being able to restore function. Surface electromyography (EMG) presents an opportunity to examine and promote human engagement at the neuromuscular level, enabling new protocols for intervention that could be combined with robotic rehabilitation, particularly when robot motion or force sensing may be unusable due to the user's impairment. In this paper, a myoelectric control interface to an exoskeleton for the elbow and wrist was evaluated on a population of ten able-bodied participants and four individuals with cervical-level SCI. The ability of an EMG classifier to discern intended direction of motion in single-degree-of-freedom (DoF) and multi-DoF control modes was assessed for usability in a therapy-like setting. The classifier demonstrated high accuracy for able-bodied participants (averages over 99% for single-DoF and near 90% for multi-DoF), and performance in the SCI group was promising, warranting further study (averages ranging from 85% to 95% for single-DoF, and variable multi-DoF performance averaging around 60%). These results are encouraging for the future use of myoelectric interfaces in robotic rehabilitation for SCI.

Ready, set, explore! Event-related potentials reveal the time-course of exploratory decisions.

The decision trade-off between exploiting the known and exploring the unknown has been studied using a variety of approaches and techniques. Surprisingly, electroencephalography (EEG) has been underused in this area of study, even though its high temporal resolution has the potential to reveal the time-course of exploratory decisions. We addressed this issue by recording EEG data while participants tried to win as many points as possible in a two-choice gambling task called a two-armed bandit. After using a computational model to classify responses as either exploitations or explorations, we examined event-related potentials locked to two events preceding decisions to exploit/explore: the arrival of feedback, and the subsequent appearance of the next trial's choice stimuli. In particular, we examined the feedback-locked P300 component, thought to index a phasic release of norepinephrine (a neural interrupt signal), and the reward positivity, thought to index a phasic release of dopamine (a neural prediction error signal). We observed an exploration-dependent enhancement of the P300 only, suggesting a critical role of norepinephrine (but not dopamine) in triggering decisions to explore. Similarly, we examined the N200/P300 components evoked by the appearance of the choice stimuli. In this case, exploration was characterized by an enhancement of the N200, but not P300, a result we attribute to increased response conflict. These results demonstrate the usefulness of combining computational and EEG methodologies, and suggest that exploratory decisions are preceded by two characterizing events: a feedback-locked neural interrupt signal (enhanced P300), and a choice-locked increase in response conflict (enhanced N200).

Dissociating the effect of flavor and nicotine in smokeless tobacco products using electroencephalography: The case of wintergreen flavors.

The increased consumption of tobacco products in recent years has been linked, among other factors, to the presence of added flavors. Although flavors are important in explaining consumption, their effects in the brain have until now been unexplored. In the present study, we investigated how electrophysiology can serve to dissociate the effects of nicotine and flavor. Participants attended 4 sessions (2-by-2 factorial design, with flavor and nicotine as within-subject factors), in each session an oddball task was performed before and after smokeless tobacco consumption. We explored the dissociation of neural responses to flavor and nicotine. While event-related potentials did not show modulation due to flavors, time-frequency showed a flavor-nicotine dissociation. Low-frequency activity (delta, theta and alpha) showed only effects of nicotine, and high-frequency activity (beta1, beta2 and gamma) showed effects only susceptible to flavor. Flavors in smokeless tobacco not only made the product more desirable but also triggered the allocation of cognitive resources. This long-lasting effect of flavor may enhance the addictive potential of the tobacco product. Further research is being developed to determine the precise role of flavors in contributing to addiction. This is the first study investigating the neural effects of flavor (specifically wintergreen) in smokeless tobacco products. By understanding the effects of flavors in the brain we can explain the precipitants of tobacco consumption behaviors, and the addictive potential of flavors. Regulators will be able to determine if and in which amount flavors should be allowed in tobacco products.

Learning From the Slips of Others: Neural Correlates of Trust in Automated Agents.

With the rise of increasingly complex artificial intelligence (AI), there is a need to design new methods to monitor AI in a transparent, human-aware manner. Decades of research have demonstrated that people, who are not aware of the exact performance levels of automated algorithms, often experience a mismatch in expectations. Consequently, they will often provide either too little or too much trust in an algorithm. Detecting such a mismatch in expectations, or trust calibration, remains a fundamental challenge in research investigating the use of automation. Due to the context-dependent nature of trust, universal measures of trust have not been established. Trust is a difficult construct to investigate because even the act of reflecting on how much a person trusts a certain agent can change the perception of that agent. We hypothesized that electroencephalograms (EEGs) would be able to provide such a universal index of trust without the need of self-report. In this work, EEGs were recorded for 21 participants (mean age = 22.1; 13 females) while they observed a series of algorithms perform a modified version of a flanker task. Each algorithm's degree of credibility and reliability were manipulated. We hypothesized that neural markers of action monitoring, such as the observational error-related negativity (oERN) and observational error positivity (oPe), are potential candidates for monitoring computer algorithm performance. Our findings demonstrate that (1) it is possible to reliably elicit both the oERN and oPe while participants monitored these computer algorithms, (2) the oPe, as opposed to the oERN, significantly distinguished between high and low reliability algorithms, and (3) the oPe significantly correlated with subjective measures of trust. This work provides the first evidence for the utility of neural correlates of error monitoring for examining trust in computer algorithms.

Speeded response errors and the error-related negativity modulate early sensory processing.

Empirical research demonstrates that when the time following error commission is constrained, subsequent sensory processing can be impaired (Buzzell et al., 2017). This reduction in sensory processing is presumably due to a bottleneck for cognitive resources produced by an overlap between error processing and subsequent stimulus processing. This finding suggests that the system dedicated to improving task performance can actually sometimes be the source of performance failures. Although this finding established that data-limited errors lead to a reduction in sensory processing at short response stimulus intervals (RSIs), it remains unclear if the relationship between error processing and subsequent sensory processing can be modulated by speeded-response errors. In the present study, event-related potentials and behavioral measures were recorded while participants performed a modified version of a Simon task, in which RSI duration was varied. We found that sensory processing, indexed by the P1 component, was reduced following errors at short (200-533 ms), but not long (866-1200 ms), RSIs. Moreover, the magnitude of error processing differentially influenced subsequent sensory processing as a function of RSI. However, whereas prior work demonstrated that the error positivity (Pe) modulated sensory processing on the subsequent trial, only the error-related negativity (ERN) did so within the Simon task. This suggests that although both data-limited errors and speeded-response errors can impact subsequent sensory processing, different stages of error processing appear to mediate this phenomenon.

Characterization of surface electromyography patterns of healthy and incomplete spinal cord injury subjects interacting with an upper-extremity exoskeleton.

Rehabilitation exoskeletons may make use of myoelectric control to restore in patients with significant motor impairment following a spinal cord injury (SCI) a sense of volitional control over their limb - a crucial component for recovery of movement. Little investigation has been done into the feasibility of using surface electromyography (sEMG) as an exoskeleton control interface for SCI patients, whose impairment manifests in a highly variable way across the patient population. We have demonstrated that by using only a small subset of features extracted from eight bipolar electrodes recording on the upper arm and forearm muscles, we can achieve high predictive accuracy for the intended direction of motion. Five healthy subjects and two SCI subjects performed voluntary isometric contractions while wearing an exoskeleton for the wrist and elbow joints, generating six distinct single and multi-DoF motions in a total of sixteen possible directions. Using linear discriminant analysis, classification performance was then evaluated using randomly selected holdout test data from the same recording session. Commonalities across subjects, both healthy and SCI, were analyzed at the levels of selected features and the values of commonly selected features. Future work will be to investigate group-specific classification of SCI subjects' intended movements for use in the real-time control of a rehabilitation exoskeleton.

Nicotine-induced and D1-receptor-dependent dendritic remodeling in a subset of dorsolateral striatum medium spiny neurons.

Nicotine is one of the most addictive substances known, targeting multiple memory systems, including the ventral and dorsal striatum. One form of neuroplasticity commonly associated with nicotine is dendrite remodeling. Nicotine-induced dendritic remodeling of ventral striatal medium spiny neurons (MSNs) is well-documented. Whether MSN dendrites in the dorsal striatum undergo a similar pattern of nicotine-induced structural remodeling is unknown. A morphometric analysis of Golgi-stained MSNs in rat revealed a natural asymmetry in dendritic morphology across the mediolateral axis, with larger, more complex MSNs found in the dorsolateral striatum (DLS). Chronic nicotine produced a lasting (at least 21day) expansion in the dendritic complexity of MSNs in the DLS, but not dorsomedial striatum (DMS). Given prior evidence that MSN subtypes can be distinguished based on dendritic morphology, MSNs were segregated into morphological subpopulations based on the number of primary dendrites. Analysis of these subpopulations revealed that DLS MSNs with more primary dendrites were selectively remodeled by chronic nicotine exposure and remodeling was specific to the distal-most portions of the dendritic arbor. Co-administration of the dopamine D1 receptor (D1R) antagonist SCH23390 completely reversed the selective effects of nicotine on DLS MSN dendrite morphology, supporting a causal role for dopamine signaling at D1 receptors in nicotine-induced dendrite restructuring. Considering the functional importance of the DLS in shaping and expressing habitual behavior, these data support a model in which nicotine induces persistent and selective changes in the circuit connectivity of the DLS that may promote and sustain addiction-related behavior.

Error-Induced Blindness: Error Detection Leads to Impaired Sensory Processing and Lower Accuracy at Short Response-Stimulus Intervals.

Empirical evidence indicates that detecting one's own mistakes can serve as a signal to improve task performance. However, little work has focused on how task constraints, such as the response-stimulus interval (RSI), influence post-error adjustments. In the present study, event-related potential (ERP) and behavioral measures were used to investigate the time course of error-related processing while humans performed a difficult visual discrimination task. We found that error commission resulted in a marked reduction in both task performance and sensory processing on the following trial when RSIs were short, but that such impairments were not detectable at longer RSIs. Critically, diminished sensory processing at short RSIs, indexed by the stimulus-evoked P1 component, was predicted by an ERP measure of error processing, the Pe component. A control analysis ruled out a general lapse in attention or mind wandering as being predictive of subsequent reductions in sensory processing; instead, the data suggest that error detection causes an attentional bottleneck, which can diminish sensory processing on subsequent trials that occur in short succession. The findings demonstrate that the neural system dedicated to monitoring and improving behavior can, paradoxically, at times be the source of performance failures.SIGNIFICANCE STATEMENT The performance-monitoring system is a network of brain regions dedicated to monitoring behavior to adjust task performance when necessary. Previous research has demonstrated that activation of the performance monitoring system following incorrect decisions serves to improve future task performance. However, the present study provides evidence that, when perceptual decisions must be made rapidly (within approximately half a second of each other), activation of the performance-monitoring system is predictive of impaired task-related attention on the subsequent trial. The data illustrate that the cognitive demands imposed by error processing can interfere with, rather than enhance, task-related attention when subsequent decisions need to be made quickly.

Neural activity reveals perceptual grouping in working memory.

There is extensive evidence that the contralateral delay activity (CDA), a scalp recorded event-related brain potential, provides a reliable index of the number of objects held in visual working memory. Here we present evidence that the CDA not only indexes visual object working memory, but also the number of locations held in spatial working memory. In addition, we demonstrate that the CDA can be predictably modulated by the type of encoding strategy employed. When individual locations were held in working memory, the pattern of CDA modulation mimicked previous findings for visual object working memory. Specifically, CDA amplitude increased monotonically until working memory capacity was reached. However, when participants were instructed to group individual locations to form a constellation, the CDA was prolonged and reached an asymptote at two locations. This result provides neural evidence for the formation of a unitary representation of multiple spatial locations.

Using Electrophysiological Measures to Assess the Consumer Acceptability of Smokeless Tobacco Products.

INTRODUCTION: Adequate evaluation of novel tobacco products must include investigation of consumers' psychological response to such products. Traditionally, subjective scales of product liking have been used to assess consumer acceptability of tobacco products. However, subjective scales may miss cognitive changes that can only be captured by direct neurophysiological assessment. The present investigation explored the viability of using electroencephalography (EEG), in combination with traditional subjective measures, to assess consumer acceptability of five smokeless tobacco products. Given previous work linking product liking to arousal/attentional (executive function) enhancement, we focused on EEG measures of attention/arousal to objectively characterize cognitive changes associated with tobacco product use. METHODS: During five separate laboratory visits, smokeless tobacco users used Verve discs, Ariva dissolvables, Skoal snuff, Camel snus, or Nicorette lozenges. The N2 and P3b event-related potential components elicited by an oddball task were used to index attentional changes before/after product usage. Additionally, resting state alpha band EEG activity was analyzed before/after product usage to index cortical arousal. RESULTS: Although analyses of the subjective results provided limited inference, analyses of the electrophysiological measures, particularly the alpha suppression measure, revealed robust differences between products. Skoal elicited significantly enhanced alpha suppression compared to all four other products tested. Additionally, alpha suppression was found to correlate positively with subjective measures of satisfaction and psychological reward, but was unrelated to perceived aversion. CONCLUSIONS: The present results provide evidence that electrophysiological measures can yield important insights into consumer acceptability of novel tobacco products and are a valuable complement to subjective measures. IMPLICATIONS: This study is the first to employ a combination of electrophysiological measures and traditional subjective assays in order to assess the consumer acceptability of smokeless tobacco products. The results highlight the importance of adopting a multidimensional/multi-method approach to studying the consumer acceptability of tobacco products.

Uncertainty-dependent activity within the ventral striatum predicts task-related changes in response strategy.

Recent neuroimaging work has demonstrated that the ventral striatum (VS) encodes confidence in perceptual decisions. However, it remains unclear whether perceptual uncertainty can signal the need to adapt behavior (such as by responding more cautiously) and whether such behavioral changes are related to uncertainty-dependent activity within the VS. Changes in response strategy have previously been observed following errors and are associated with both medial frontal cortex (MFC) and VS, two components of the performance-monitoring network. If uncertainty can elicit changes in response strategy (slowing), then one might hypothesize that these changes rely on the performance-monitoring network. In the present study, we investigated the link between perceptual uncertainty and task-related behavioral adaptations (response slowing and accuracy increases), as well as how such behavioral changes relate to uncertainty-dependent activity within MFC and VS. Our participants performed a two-choice perceptual decision-making task in which perceptual uncertainty was reported on each trial while behavioral and event-related functional magnetic resonance imaging data were collected. Analysis of the behavioral data revealed that uncertain (but correct) responses led to slowing on subsequent trials, a phenomenon that was positively correlated with increased accuracy. Critically, post-uncertainty slowing was negatively correlated with the VS activity elicited by uncertain responses. In agreement with previous reports, increases in MFC activation were observed for uncertain responses, although MFC activity was not correlated with post-uncertainty slowing. These results suggest that perceptual uncertainty can serve as a signal to adapt one's response strategy and that such behavioral changes are closely tied to the VS, a key node in the performance-monitoring network.

Adolescent nicotine induces persisting changes in development of neural connectivity.

Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered. We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part through D1DR receptors, in a network activated by nicotine. The adolescent nicotine effects reviewed here suggest that modification of late CNS development constitutes a hazard of adolescent nicotine use.

Role of the D3 dopamine receptor in nicotine sensitization.

Adolescent cigarette use is associated with reduced quitting success and continued smoking in adulthood. Interestingly, polymorphisms of the dopamine D3 receptor (DRD3) gene have been associated with smoking behavior, and the receptor is expressed in an age- and brain region-dependent manner that suggests relevance to addiction. Here, we investigate the possible role of dopamine-related receptors, including DRD3 and an intriguing splice variant known as D3nf, in nicotine-induced sensitization. In adolescent and adult male rats, we examined (1) alterations occurring in dopamine receptor-related mRNAs (DRD1, DRD2, DRD3 and D3nf) at two time points during a sensitizing regimen of nicotine and (2) whether DRD3 antagonism either during the initial treatment (induction) or at a later challenge exposure (expression) is able to block nicotine sensitization. Nicotine-induced changes were seen for DRD3 and D3nf mRNAs in the nucleus accumbens shell early in repeated exposure in both age groups. DRD3 antagonism only blocked the induction of sensitization in adolescents and did not block the expression of sensitization in either age group. Adolescents and adults showed opposite DRD1 mRNA responses to nicotine treatment, while no age- and nicotine-related changes in DRD2 mRNA were observed. These data reveal important age-dependent regulation of DRD1- and DRD3-related mRNAs during the course of nicotine exposure. Furthermore, they highlight a requirement for DRD3 signaling in the development of adolescent nicotine sensitization, suggesting it may represent an appropriate target in the prevention of nicotine dependence initiated at this age.