Opposing Motor Memories in the Direct and Indirect Pathways of the Basal Ganglia.

Loss of dopamine neurons causes motor deterioration in Parkinson's disease patients. We have previously reported that in addition to acute motor impairment, the impaired motor behavior is encoded into long-term memory in an experience-dependent and task-specific manner, a phenomenon we refer to as aberrant inhibitory motor learning. Although normal motor learning and aberrant inhibitory learning oppose each other and this is manifested in apparent motor performance, in the present study, we found that normal motor memory acquired prior to aberrant inhibitory learning remains preserved in the brain, suggesting the existence of independent storage. To investigate the neuronal circuits underlying these two opposing memories, we took advantage of the RNA-binding protein YTHDF1, an m 6 A RNA methylation reader involved in the regulation of protein synthesis and learning/memory. Conditional deletion of Ythdf1 in either D1 or D2 receptor-expressing neurons revealed that normal motor memory is stored in the D1 (direct) pathway of the basal ganglia, while inhibitory memory is stored in the D2 (indirect) pathway. Furthermore, fiber photometry recordings of GCaMP signals from striatal D1 (dSPN) and D2 (iSPN) receptor-expressing neurons support the preservation of normal memory in the direct pathway after aberrant inhibitory learning, with activities of dSPN predictive of motor performance. Finally, a computational model based on activities of motor cortical neurons, dSPN and iSPN neurons, and their interactions through the basal ganglia loops supports the above observations. These findings have important implications for novel approaches in treating Parkinson's disease by reactivating preserved normal memory, and in treating hyperkinetic movement disorders such as chorea or tics by erasing aberrant motor memories.

A cholinergic circuit that relieves pain despite opioid tolerance.

Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through ⍺7 nicotinic acetylcholine receptors (nAChRs). Activating ⍺7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca2+ and peroxisome proliferator-activated receptor α (PPAR⍺)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that ⍺7 nAChR-mediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.

The Long and Winding Road: 25 Years of the National Advanced Driving Simulator.

The National Advanced Driving Simulator is a high-fidelity motion-base simulator owned by the National Highway Transportation Safety Administration and managed and operated by the University of Iowa. Its 25-year history has intersected with some of the most significant developments in automotive history, such as advanced driver assistance systems like stability control and collision warning systems, and highly automated vehicles. The simulator is an application of immersive virtual reality that uses multiprojection instead of head-mounted displays. A large-excursion motion system provides realistic acceleration and rotation cues to the driver. Due to its level of immersion and realism, drivers respond to events in the simulator the same way they would in their own vehicle. We document the history and technology behind this national facility.

Quantifying and recommending seat belt reminder timing using naturalistic driving video data.

INTRODUCTION: To better understand the timing of when people buckle their seat belt, an analysis of a naturalistic driving study was used. The study provided a unique perspective inside of the vehicle where the entire seat belt was visible from the time the driver entered the vehicle to one minute of driving forward or 32 kph. METHOD: Seat belt buckling behavior was identified for 30 drivers. An additional 10 drives for 13 of these drivers were identified for a seat belt sequencing, which identified the points when the vehicle was put into ignition, shifted, when vehicle movement began, and when the seat belt was buckled. The speed at belt closure was also identified. The timing from ignition to buckle and to shifting into forward gear were examined to identify the speed and appropriate timing for seat belt reminders. RESULTS: The data show that drivers were buckled in over 92% of the 3,102 drives. In addition, in 70% of those total drives, the drivers were buckled before the vehicle began movement. Of greater interest for seat belt reminders/interlocks are those drives when drivers buckle after movement. When considering time from ignition to seat belt closure, the mean was 27.5 s. Because higher speeds are typically reached when traveling forward rather than reverse, it was important to know the time duration from shifting into drive to buckling. With this consideration, the mean to buckle dropped to 16.2 s. The mean speed at buckling when traveling forward was 15.3 kph. From the regression analysis, the input variables 'Age,' 'Sex,' 'Weight,' 'Environment,' and 'Weather' are significant contributors in predicting the log odds of a driver putting on seatbelt. CONCLUSIONS: With the understanding that higher speeds lead to an increased risk of injury and/or death and with the results of the analysis, a recommendation of a 30 s time from forward shift and a 25 kph (6.9 m/s) threshold for reminder systems should be implemented. The regression analysis also validates that most of the predicted seat belt buckling times are within 30 s. Practical Applications: This would reduce perception of nuisance alerts and protect the driver from higher speed unbuckled crashes. The seat belt buckling time prediction model also demonstrates good potential for developing tailored buckling warning system for different drivers.

Perceived effects of cannabis: Generalizability of changes in driving performance.

OBJECTIVE: The objective of this analysis was to determine the generalizability of the relationship between different samples of a driver's perceived state after cannabis use and related performance while operating a motor vehicle. METHODS: Data were collected from 52 subjects in a study examining the effects of cannabis on driving performance. Data were analyzed using the SAS GLM Select procedure, using stepwise selection, with subjective effects, dosing condition (placebo vs. 6.18% delta-9-tetrahydrocannabinol [THC]), and driving context as independent measures. Correlation matrices of measures of driving performance against subjective responses and dosing condition used Pearson's and Spearman's test statistics, respectively. Results were compared to a prior study from a sample of 10 subjects. RESULTS: Subjective perceptions of acute cannabis impairment remain significant predictors of driving performance and explain individual variability in driving performance degradation as well as the data, beyond that which can be explained by acute use of cannabis alone. However, the significant subjective predictors of driving performance differ between the current and prior studies. To better understand these differences, correlations between subjective effects and performance measures were evaluated, which revealed that most correlations matched directionally (e.g., an increase in "good drug effect" was correlated with an increase in standard deviation of lane position [SDLP]). When there was a mismatch, 1 or more correlations were insignificant. Dosing condition and "stoned" were perfectly consistent; "high" and "sedated" contained 1 mismatch; and "anxious," "good drug effect" and "restless" contained 3 or more mismatches. CONCLUSIONS: The results indicate that across both studies, differences in the perceived effects of cannabis are reflected in changes in both lateral and longitudinal control beyond the acute effects of cannabis, which may help explain individual variability in response to acute intoxication. However, the generalizability of these findings is lacking, as shown by inconsistencies in when and where subjective effects were significant. Other factors such as frequency of use, usage type, the evolving profile of a cannabis user, as well as other individual differences should be considered to explain this additional variability.

Partial connectomes of labeled dopaminergic circuits reveal non-synaptic communication and axonal remodeling after exposure to cocaine.

Dopaminergic (DA) neurons exert profound influences on behavior including addiction. However, how DA axons communicate with target neurons and how those communications change with drug exposure remains poorly understood. We leverage cell type-specific labeling with large volume serial electron microscopy to detail DA connections in the nucleus accumbens (NAc) of the mouse (Mus musculus) before and after exposure to cocaine. We find that individual DA axons contain different varicosity types based on their vesicle contents. Spatially ordering along individual axons further suggests that varicosity types are non-randomly organized. DA axon varicosities rarely make specific synapses (<2%, 6/410), but instead are more likely to form spinule-like structures (15%, 61/410) with neighboring neurons. Days after a brief exposure to cocaine, DA axons were extensively branched relative to controls, formed blind-ended 'bulbs' filled with mitochondria, and were surrounded by elaborated glia. Finally, mitochondrial lengths increased by ~2.2 times relative to control only in DA axons and NAc spiny dendrites after cocaine exposure. We conclude that DA axonal transmission is unlikely to be mediated via classical synapses in the NAc and that the major locus of anatomical plasticity of DA circuits after exposure to cocaine are large-scale axonal re-arrangements with correlated changes in mitochondria.

Mechanisms of cannabis impairment: Implications for modeling driving performance.

Past research on cannabis has been limited in scope to THC potencies lower than legally available and efforts to integrate the effects into models of driving performance have not been attempted to date. The purpose of this systematic review is to understand the implications for modeling driving performance and describe future research needs. The risk of motor vehicle crashes increases 2-fold after smoking marijuana. Driving during acute cannabis intoxication impairs concentration, reaction time, along with a variety of other necessary driving-related skills. Changes to legislation in North America and abroad have led to an increase in cannabis' popularity. This has given rise to more potent strains, with higher THC concentrations than ever before. There is also rising usage of novel ingestion methods other than smoking, such as oral cannabis products (e.g., brownies, infused drinks, candies), vaping, and topicals. The PRISMA guidelines were followed to perform a systematic search of the PubMed database for peer-reviewed literature. Search terms were combined with keywords for driving performance: driving, performance, impairment. Grey literature was also reviewed, including congressional reports, committee reports, and roadside surveys. There is a large discrepancy between the types of cannabis products sold and what is researched. Almost all studies that used inhalation as the mode of ingestion with cannabis that is around 6% THC. This pales in comparison to the more potent strains being sold today which can exceed 20%. Which is to say nothing of extracts, which can contain 60% or more THC. Experimental protocol is another gap in research that needs to be filled. Methodologies that involve naturalistic (real world) driving environments, smoked rather than vaporized cannabis, and non-lab certified products introduce uncontrollable variables. When considering the available literature and the implications of modeling the impacts of cannabis on driving performance, two critical areas emerge that require additional research: The first is the role of cannabis potency. Second is the route of administration. Does the lower peak THC level result in smaller impacts on performance? How long does potential impairment last along the longer time-course associated with different pharmacokinetic profiles. It is critical for modeling efforts to understand the answers to these questions, accurately model the effects on driver performance, and by extension understand the risk to the public.

Examining the Association Between Age and Tractor Driving Performance Measures Using a High-Fidelity Tractor Driving Simulator.

HIGHLIGHTS This study uses a new tractor driving simulator to examine the impact of age on perception response time in an emergency braking situation. The results demonstrate increased risk for crash among older farm equipment operators. ABSTRACT. Transportation-related incidents are the leading cause of occupational fatalities for all industries in the U.S. In the agriculture industry, where tractor-related incidents are the leading cause of occupational fatality, fatal crashes occur more frequently among senior farm equipment operators (FEOs) than younger FEOs. This study examined the association between age and driving performance among FEOs using a simulated driving environment. We demonstrated that older FEOs have longer perception response times when encountering an incurring semi-truck during a simulated drive than younger FEOs. These results persisted when adjusted for selected medical diagnoses and medications, tractor generation, and tractor horsepower. However, due to the small sample size and limitations of the tractor driving simulator, its use for event perception response time research is questionable. The tractor driving simulator used in this study may be better suited for distracted driving studies and studies comparing the ways in which FEOs drive passenger vehicles compared to tractors.

Modeling and prediction of driving performance measures based on multi-output convolutional Gaussian process.

Driving performance measures (DPMs) are important indices for driving and personal safety in vehicle operation. The DPMs are collected under various controlled driving conditions to demonstrate different driving behaviors so that mitigating technology interventions can be studied and designed. However, significant costs are involved in the DPM acquisition, and there are a very limited number of controlled driving condition data. Thus, the modeling and prediction of the DPMs under unobserved driving conditions are critical, and many methods have been developed. However, existing literature in this area suffer a common limitation: The interactions among different DPMs are not fully considered (each DPM is modeled individually), although the existence of such interactions is widely reported. This paper proposes a novel DPM modeling and prediction method, i.e., multi-output convolutional Gaussian process (MCGP), that incorporates the interactions among different DPMs. The method features the modeling flexibility for different DPMs and the interpretable modeling structure for integrating the DPM interactions. The method is compared with three benchmark methods on the DPM data set under four different settings, and the results demonstrate the superiorities of the method. Discussions and interpretations of the results are also provided.

Perceived effects of cannabis and changes in driving performance under the influence of cannabis.

OBJECTIVE: Reports indicate that cannabis users will adapt their driving to compensate for the perceived drug effects of cannabis. This analysis examined the relationship between driver perceptions of their state contrasted with objective measures of their performance while operating a motor vehicle. METHODS: Data was collected from ten subjects in a study examining the effects of cannabis on driving performance. Driving performance was collected on the NADS quarter-cab miniSim, a limited field of view non-motion simulator, approximately two hours after cannabis inhalation. Driving measures of both lateral and longitudinal control were included in our analysis. Subjective measures of the effects of cannabis were collected at peak and prior to driving, using visual analog scales. Data were analyzed using the SAS GLM Select procedure with subjective effect, dosing condition (placebo vs 6.9% THC), and driving event as independent measures. The stepwise selection method was used. RESULTS: The analysis of each of the subjective effects showed significant differences between the placebo and the active cannabis dosed conditions. While we found variance in difference between group means, there was greater variability between subject values. We found that subjective measures were predictive of variance in driver inputs, such as steering frequency and steering reversal rate. Variance in SDLP and other driving performance measures, however, were predicted by dosing condition. CONCLUSIONS: Overall, some of the effects perceived by the driver were better related to changes in driver inputs rather than the presence of cannabis itself. Changes in performance measures such as SDLP are better explained by dosing condition. Thus, driver's perceptions may result in changes to driving behavior that could mitigate the effect of cannabis. For both lateral and longitudinal control, an increasing perception of stimulation produced a positive effect on performance. Our results provide a better understanding of how different strains of cannabis, which produce different subjective experiences for users, could impact driving safety. Specifically, we found drug effects that produce more stimulation results in less impact on driving, while those that produce a more stoned or high feeling results in a greater negative effect on driving.

Benefits estimation of regenerative braking versus service braking.

A central question not yet examined in the literature is whether regenerative braking provides a kinematic deceleration safety advantage in time and distance over traditional service braking. This research explores three conditions of braking (traditional service braking, low level of regenerative braking, and high level of regenerative braking) to determine any safety advantages regenerative braking offers. Thirty participants took part in a simulator study with a between-subjects study design, allocating 10 participants per condition. The study drive took place in a simulator and involved three braking events. The results showed a significant difference between the means of the three conditions for average deceleration of the vehicle in the time interval between the driver releasing the accelerator and pressing the brake for all three events showing RB did provide the drivers with a braking advantage. When events 1 and 2 were combined, there was also significance with maximum brake force. Practitioner summary: This research looked to determine whether regenerative braking provides a deceleration safety advantage over traditional service braking. The results showed RB did provide the drivers with a braking advantage. The results also showed driver foot behaviour differed with the RB High condition.

Examination of Realism in a High-fidelity Tractor Driving Simulator.

Transportation-related incidents are the leading cause of occupational fatalities for all industries in the U.S., including the agricultural industry, which suffers thou- sands of crashes involving farm equipment each year. Simulated driving studies offer a safe and cost-effective way to conduct driving research that would not be feasible in the real world. A tractor driving miniSim was developed and then evaluated for realism at the University of Iowa among 99 Midwestern farm equipment operators. It is important for driving simulators to have a high degree of realism for their results to be applicable to non-simulated driving operations. High-fidelity driving simulators facilitate extrapolations made by driving research but should be re-tested for realism when changes are made to the design of the simulator. The simulator used in this study emulated a tractor cab with realistic controls, three high-resolution screens, and high-fidelity sound. After completing a 10-minute drive, farm equipment operators completed a survey and scored four specific domains assessing specific characteristics (i.e., appearance, user interface, control, and sound) of the tractor simulator's realism using a seven-point Likert scale (from 0 = not at all realistic to 6 = completely realistic). An overall realism score and domain scores were calculated. Farm equipment operators were also asked to provide recommendations for improving the tractor miniSim. Overall, farm equipment operators rated the simulator's realism favorably (i.e., >3 on a scale from 0 to 6) for all individual items and domains. The appearance domain received the highest average realism score (mean = 4.58, SD = 1.03), and the sound domain received the lowest average realism score (mean = 3.86, SD = 1.57). We found no significant differences in realism scores across farm equipment operator characteristics. The most frequently suggested improvements were to tighten the steering wheel (27%), make the front tires visible (19%), and that no improvements were needed to improve the simulator realism (18%). This study demonstrates that the new trac- tor miniSim is a viable approach to studying farm equipment operations and events that can lead to tractor-related crashes. Future studies should incorporate the suggested improvements and seek to validate the simulator as a research and outreach instrument.

Classifying and predicting risky driving among novice drivers: A group-based trajectory approach.

INTRODUCTION: Classifying risky driving among new teenage drivers is important for efficiently targeting driving interventions. We thoroughly investigated whether novice drivers can be clustered by their driving outcome profiles over time. METHODS: A sample of 51 newly licensed teen drivers was recruited and followed over a period of 20 weeks. An in-vehicle video recording system was used to gather data on dangerous driving events referred to as DDEs (elevated g-force, near-crash, and crash events), risky driving behaviors referred to as RDBs (e.g., running stop signs, cell phone use while driving), and miles traveled. The DDE and RDB weekly rates rate were determined by dividing the number of DDEs and RDBs in a week by the number of miles traveled in that week, respectively. Group-based trajectory modeling was used to map the clustering of DDE rate and RDB rate patterns over time and their associated covariates. RESULTS: Two distinct DDE rate patterns were found. The first group (69.1% of the study population) had a lower DDE rate which was consistent over time. The second had a higher DDE rate pattern (30.9%) and characterized by a rising trend in DDE rate followed by a steady decrease (inverted U-shaped pattern). Two RDB rate patterns were also identified: a lower RDB rate pattern (83.4% of the study population) and a higher RDB rate pattern (16.6%). RDB and DDE rate patterns were positively related, and therefore, co-occurred. The results also showed that males were more likely than females to be in the higher DDE and RDB rate patterns. CONCLUSION: The groups identified by trajectory models may be useful for targeting driving interventions to teens that would mostly benefit as the different trajectories may represent different crash risk levels. Practical applications: Parents using feedback devices to monitor the driving performance of their teens can use the initial weeks of independent driving to classify their teens as low or high-risk drivers. Teens making a very few DDEs during their early weeks of independent driving are likely to remain in the lower risk group over time and can be spared from monitoring and interventions. However, teens making many DDEs during their initial weeks of unsupervised driving are likely to continue to make even more DDEs and would require careful monitoring and targeted interventions.

Auditory Global Positioning System and Advanced Driver Assistance Systems: A Safer Alternative to Bioptic Telescopes for Drivers Who Are Visually Impaired?

This work challenges the standard of the past 40 years, which required the use of a bioptic telescope by individuals with vision loss wanting to be licensed to drive in most states in the United States.Driving continues to be the key to independence for many individuals, particularly older drivers who live in an area where public transportation is limited or nonexistent. For the past 40 years, the most frequently option to allow drivers who are visually impaired to maintain driving privileges was to require them to use a bioptic telescope. Bioptic telescopes were felt to be necessary for wayfinding when driving. In addition, it was thought that a person could look through a bioptic telescope and still be aware of the driving environment around him/her. Human factor research has shown that the assertion that an individual can attend to two tasks simultaneously is not possible. Taking one's eyes off the road for as little as 2 seconds can lead to lane position breakdown. In 2018, wayfinding can now be more easily accomplished with the use of ubiquitous technologies like Global Positioning System systems on our telephones and in our cars. Driver distraction principles support safer alternatives to bioptic telescopes because these audio options allow the drivers to maintain their eyes and their attention on the road and the traffic around them. The switching of view within the bioptic spectacles is attentionally demanding, and the visual field restriction of such devices reduces overall situation awareness by narrowing the driver's attention.

Teen driver system modeling: a tool for policy analysis.

BACKGROUND: Motor vehicle crashes remain the leading cause of teen deaths in spite of preventive efforts. Prevention strategies could be advanced through new analytic approaches that allow us to better conceptualize the complex processes underlying teen crash risk. This may help policymakers design appropriate interventions and evaluate their impacts. METHODS: System Dynamics methodology was used as a new way of representing factors involved in the underlying process of teen crash risk. Systems dynamics modeling is relatively new to public health analytics and is a promising tool to examine relative influence of multiple interacting factors in predicting a health outcome. Dynamics models use explicit statements about the process being studied and depict how the elements within the system interact; this usually leads to discussion and improved insight. A Teen Driver System Model was developed by following an iterative process where causal hypotheses were translated into systems of differential equations. These equations were then simulated to test whether they can reproduce historical teen driving data. The Teen Driver System Model that we developed was calibrated on 47 newly-licensed teen drivers. These teens were recruited and followed over a period of 5-months. A video recording system was used to gather data on their driving events (elevated g-force, near-crash, and crash events) and miles traveled. RESULTS: The analysis suggests that natural risky driving improvement curve follows a course of a slow improvement, then a faster improvement, and finally a plateau: that is, an S-shaped decline in driving events. Individual risky driving behavior depends on initial risk and driving exposure. Our analysis also suggests that teen risky driving improvement curve is created endogenously by several feedback mechanisms. A feedback mechanism is a chain of variables interacting with each other in such a way they form a closed path of cause and effect relationships. CONCLUSIONS: Teen risky driving improvement process is created endogenously by several feedback mechanisms. The model proposed in the present article to reflect this improvement process can spark discussion, which may pinpoint to additional processes that can benefit from further empirical research and result in improved insight.

Nicotine aversion is mediated by GABAergic interpeduncular nucleus inputs to laterodorsal tegmentum.

Nicotine use can lead to dependence through complex processes that are regulated by both its rewarding and aversive effects. Recent studies show that aversive nicotine doses activate excitatory inputs to the interpeduncular nucleus (IPN) from the medial habenula (MHb), but the downstream targets of the IPN that mediate aversion are unknown. Here we show that IPN projections to the laterodorsal tegmentum (LDTg) are GABAergic using optogenetics in tissue slices from mouse brain. Selective stimulation of these IPN axon terminals in LDTg in vivo elicits avoidance behavior, suggesting that these projections contribute to aversion. Nicotine modulates these synapses in a concentration-dependent manner, with strong enhancement only seen at higher concentrations that elicit aversive responses in behavioral tests. Optogenetic inhibition of the IPN-LDTg connection blocks nicotine conditioned place aversion, suggesting that the IPN-LDTg connection is a critical part of the circuitry that mediates the aversive effects of nicotine.

Examining teen driver crashes and the prevalence of distraction: Recent trends, 2007-2015.

INTRODUCTION: Teen drivers crash at a much higher rate than adult drivers, with distractions found as a factor in nearly 6 out of 10 moderate-to-severe teen crashes. As the driving environment continues to rapidly evolve, it is important to examine the effect these changes may be having on our youngest and most vulnerable drivers. METHOD: The purpose of this study was to identify types of vehicle crashes teens are most frequently involved in, as well as the distracting activities being engaged in leading up to these crashes, with a focus on identifying changes or trends over time. We examined 2,229 naturalistic driving videos involving drivers ages 16-19. These videos captured crashes occurring between 2007 and 2015. The data of interest for this study included crash type, behaviors drivers engaged in leading up to the collision, total duration of time the driver's eyes were off the forward roadway, and duration of the longest glance away from forward. RESULTS: Rear-end crashes increased significantly (annual % change=3.23 [2.40-4.05]), corresponding with national data trends. Among cell phone related crashes, a significant shift occurred, from talking/listening to operating/looking (annual % change=4.22 [1.15-7.29]). Among rear-end crashes, there was an increase in the time drivers' eyes were off the road (ß=0.1527, P=0.0004) and durations of longest glances away (ß=0.1020, P=0.0014). CONCLUSIONS: Findings suggest that shifts in the way cell phones are being used, from talking/listening to operating/looking, may be a cause of the increasing number of rear-end crashes for teen drivers. PRACTICAL APPLICATIONS: Understanding the role that cell phone use plays in teen driver crashes is extremely important. Knowing how and when teens are engaging in this behavior is the only way effective technologies can be developed for mitigating these crashes.

Evaluating variability in foot to pedal movements using functional principal components analysis.

There are reasons why the driver's foot may not be applied to the correct pedal while driving and this can lead to unintended consequences. In this study, we seek to capture common and unique patterns of variations in drivers' foot movements using functional principal components analysis (FPCA). This analysis technique was used to analyze three categories of pedal response types (direct hits, corrected trajectories, and pedal errors) based on the various foot to pedal trajectories. Data from a driving simulator study with video data of foot movements for 45 drivers was used for analyses. Most foot movements show common patterns associated with direct hits and corrected trajectories with some level of variation. However, those foot movements associated with unique patterns might be early indicators of pedal errors. The findings of this study can be used with collision mitigation systems to provide early detection of foot trajectories that are more likely to result in a pedal error.

Nicotinic modulation of descending pain control circuitry.

Along with the well-known rewarding effects, activation of nicotinic acetylcholine receptors (nAChRs) can also relieve pain, and some nicotinic agonists have analgesic efficacy similar to opioids. A major target of analgesic drugs is the descending pain modulatory pathway, including the ventrolateral periaqueductal gray (vlPAG) and the rostral ventromedial medulla (RVM). Although activating nAChRs within this circuitry can be analgesic, little is known about the subunit composition and cellular effects of these receptors, particularly within the vlPAG. Using electrophysiology in brain slices from adult male rats, we examined nAChR effects on vlPAG neurons that project to the RVM. We found that 63% of PAG-RVM projection neurons expressed functional nAChRs, which were exclusively of the α7-subtype. Interestingly, the neurons that express α7 nAChRs were largely nonoverlapping with those expressing µ-opioid receptors (MOR). As nAChRs are excitatory and MORs are inhibitory, these data suggest distinct roles for these neuronal classes in pain modulation. Along with direct excitation, we also found that presynaptic nAChRs enhanced GABAergic release preferentially onto neurons that lacked α7 nAChRs. In addition, presynaptic nAChRs enhanced glutamatergic inputs onto all PAG-RVM projection neuron classes to a similar extent. In behavioral testing, both systemic and intra-vlPAG administration of the α7 nAChR-selective agonist, PHA-543,613, was antinociceptive in the formalin assay. Furthermore, intra-vlPAG α7 antagonist pretreatment blocked PHA-543,613-induced antinociception via either administration method. Systemic administration of submaximal doses of the α7 agonist and morphine produced additive antinociceptive effects. Together, our findings indicate that the vlPAG is a key site of action for α7 nAChR-mediated antinociception.