A Brief Screening Tool for Risk of Self-Medication of Pain with Substance Use.

OBJECTIVES: Substance use and pain are both growing public health concerns globally. Evidence suggests that individuals may use substances in order to self-medicate their pain. The Catastrophizing, Anxiety, Negative Urgency, and Expectancy model was developed to provide a theoretical foundation for the modifiable risk factors implicated in self-medication of pain with substance use. This study aimed to use the outcomes in the Catastrophizing, Anxiety, Negative Urgency, and Expectancy model to develop a brief clinical screening tool to identify individuals at risk for self-medication. METHODS: Participants (N = 520; Mage = 38.8) were adults who endorsed the past three-month use of at least one substance and completed an online questionnaire. Logistic regression and receiver operator characteristic analyses were used to reduce the initial 104-item questionnaire to the items needed to achieve a minimum accuracy score of 0.95 and 0.90. RESULTS: A 14-item and a 7-item questionnaire were derived from the initial larger questionnaire. Both of these questionnaires were significantly correlated with the outcome variables and were significantly associated with health risk and percent of use because of pain. The R2 values between the 14- and 7-item versions were only significantly different for the percent of alcohol use because of pain. CONCLUSIONS: The study provides two brief screening tools to screen for individuals at risk for self-medication of pain with substance use that can be easily implemented within clinical settings. Further, the screening tools provide insight into modifiable risk factors for self-medication and may also be valuable to monitor treatment response.

Modeling Effects of Variable preBötzinger Complex Network Topology and Cellular Properties on Opioid-Induced Respiratory Depression and Recovery.

The preBötzinger complex (preBötC), located in the medulla, is the essential rhythm-generating neural network for breathing. The actions of opioids on this network impair its ability to generate robust, rhythmic output, contributing to life-threatening opioid-induced respiratory depression (OIRD). The occurrence of OIRD varies across individuals and internal and external states, increasing the risk of opioid use, yet the mechanisms of this variability are largely unknown. In this study, we utilize a computational model of the preBötC to perform several in silico experiments exploring how differences in network topology and the intrinsic properties of preBötC neurons influence the sensitivity of the network rhythm to opioids. We find that rhythms produced by preBötC networks in silico exhibit variable responses to simulated opioids, similar to the preBötC network in vitro. This variability is primarily due to random differences in network topology and can be manipulated by imposed changes in network connectivity and intrinsic neuronal properties. Our results identify features of the preBötC network that may regulate its susceptibility to opioids.

Latent neural population dynamics underlying breathing, opioid-induced respiratory depression and gasping.

Breathing is vital and must be concurrently robust and flexible. This rhythmic behavior is generated and maintained within a rostrocaudally aligned set of medullary nuclei called the ventral respiratory column (VRC). The rhythmic properties of individual VRC nuclei are well known, yet technical challenges have limited the interrogation of the entire VRC population simultaneously. Here we characterize over 15,000 medullary units using high-density electrophysiology, opto-tagging and histological reconstruction. Population dynamics analysis reveals consistent rotational trajectories through a low-dimensional neural manifold. These rotations are robust and maintained even during opioid-induced respiratory depression. During severe hypoxia-induced gasping, the low-dimensional dynamics of the VRC reconfigure from rotational to all-or-none, ballistic efforts. Thus, latent dynamics provide a unifying lens onto the activities of large, heterogeneous populations of neurons involved in the simple, yet vital, behavior of breathing, and well describe how these populations respond to a variety of perturbations.

Effect of typical alcohol use and expectancies on the social manipulation of drinking behavior in a virtual bar pilot study.

BACKGROUND: Recent work indicates that increasing the drinking rate of a virtual bar-goer (VB) increases the rate of drinking for participants in a virtual reality (VR) bar environment. Here, we test the hypothesis that biopsychosocial factors including typical drinking pattern and expectancy that alcohol enhances social interactions would moderate this effect. METHODS: We assessed the drinking topography (DT) of participants (N=20) in a VR environment with a programmable VB during two testing sessions: one with a fast-drinking VB (30-60s sip interval) and one in which the VB drank slowly (60-120s sip interval). In this secondary analysis, linear mixed models were used to characterize potential interactions of typical daily alcohol intake (quantity-frequency index [QFI]), maximal alcohol consumed in one bout over the past six months (maxQ), Alcohol Use Disorder Identification Test (AUDIT) score, and expectancy that alcohol enhances social and physical pleasures (SPP) with time in simulation and condition on sip interval and volume. RESULTS: Individuals with higher MaxQ showed a reduced effect of time on sip volume such that more intense recent binge episodes were associated with consistent drinking. Greater AUDIT scores were associated with lower sip intervals. In addition, greater SPP expectancy was associated with higher sip volumes, but only in the fast-drinking VB condition. CONCLUSIONS: Greater drinking behavior and social expectancies were associated with more rapid drinking topography. In addition, findings suggest challenging alcohol outcome expectancies related to social enhancement could reduce alcohol-related risks by slowing the rate of alcohol intake in social situations.

Does treating pain with alcohol affect drinking reduction among women with HIV enrolled in a clinical trial of naltrexone?

BACKGROUND: Many women living with HIV (WLWH) experience pain. Alcohol use with the intent to treat pain could lead to hazardous drinking and difficulty in reducing drinking. Naltrexone acts on opioid receptors important for pain regulation and is an approved treatment for alcohol use disorder. In this secondary analysis of a randomized double-blind placebo-controlled naltrexone clinical trial, the goals were to (1) compare alcohol reduction between women who drank to treat pain and those who did not and (2) examine differences in alcohol reduction by both drinking intention and treatment arm. METHODS: Women living with HIV (N = 194, mean age 48.3 years, 83% non-Hispanic Black, 11% Hispanic) with hazardous drinking (>7 drinks/week) were randomized to receive daily treatment with naltrexone 50 mg or placebo for 4 months. Study visits occurred at baseline and 2, 4, and 7 months (posttreatment). The number of drinks/week was measured using the Timeline Follow Back. Use of alcohol to treat pain was self-reported. Participants were categorized as using alcohol to treat pain or not and in the naltrexone or placebo group. Chi-square, t-test, MANOVA, and sequential mixed effects models were used to determine group differences in demographic factors, mean/drinks per week, and percent change in mean drinks/week at baseline and each follow-up visit. RESULTS: There was a consistent decrease in drinking throughout the study. There was not a significant difference in mean drinks/week at any point in the study between women who used alcohol to treat pain and those who did not. When considering treatment arm, at 2 months only those who did not use alcohol to treat pain in the naltrexone group had a significantly lower mean drinks/week than the other groups (p = 0.007); all groups had similar decreases in drinking from 4 months onward. CONCLUSION: In the naltrexone group, WLWH who drank to treat pain reduced their alcohol consumption more slowly than WLWH who did not drink to treat pain. Replication of these findings would suggest that alcohol treatment guidelines should address pain as a factor in drinking outcomes.

Elevated susceptibility to exogenous seizure triggers and impaired interneuron excitability in a mouse model of Leigh syndrome epilepsy.

Mutations in the NADH dehydrogenase (ubiquinone reductase) iron­sulfur protein 4 (NDUFS4) gene, which encodes for a key structural subunit of the OXFOS complex I (CI), lead to the most common form of mitochondrial disease in children known as Leigh syndrome (LS). As in other mitochondrial diseases, epileptic seizures constitute one of the most significant clinical features of LS. These seizures are often very difficult to treat and are a sign of poor disease prognosis. Mice with whole-body Ndufs4 KO are a well-validated model of LS; they exhibit epilepsy and several other clinical features of LS. We have previously shown that mice with Ndufs4 KO in only GABAergic interneurons (Gad2-Ndufs4-KO) reproduce the severe epilepsy phenotype observed in the global KO mice. This observation indicated that these mice represent an excellent model of LS epilepsy isolated from other clinical manifestations of the disease. To further characterize this epilepsy phenotype, we investigated seizure susceptibility to selected exogenous seizure triggers in Gad2-Ndufs4-KO mice. Then, using electrophysiology, imaging, and immunohistochemistry, we studied the cellular, physiological, and neuroanatomical consequences of Ndufs4 KO in GABAergic interneurons. Homozygous KO of Ndufs4 in GABAergic interneurons leads to a prominent susceptibility to exogenous seizure triggers, impaired interneuron excitability and interneuron loss. Finally, we found that the hippocampus and cortex participate in the generation of seizure activity in Gad2-Ndufs4-KO mice. These findings further define the LS epilepsy phenotype and provide important insights into the cellular mechanisms underlying epilepsy in LS and other mitochondrial diseases.

Purinergic signaling mediates neuroglial interactions to modulate sighs.

Sighs prevent the collapse of alveoli in the lungs, initiate arousal under hypoxic conditions, and are an expression of sadness and relief. Sighs are periodically superimposed on normal breaths, known as eupnea. Implicated in the generation of these rhythmic behaviors is the preBötzinger complex (preBötC). Our experimental evidence suggests that purinergic signaling is necessary to generate spontaneous and hypoxia-induced sighs in a mouse model. Our results demonstrate that driving calcium increases in astrocytes through pharmacological methods robustly increases sigh, but not eupnea, frequency. Calcium imaging of preBötC slices corroborates this finding with an increase in astrocytic calcium upon application of sigh modulators, increasing intracellular calcium through g-protein signaling. Moreover, photo-activation of preBötC astrocytes is sufficient to elicit sigh activity, and this response is blocked with purinergic antagonists. We conclude that sighs are modulated through neuron-glia coupling in the preBötC network, where the distinct modulatory responses of neurons and glia allow for both rhythms to be independently regulated.

Task-dependent functional connectivity of pain is associated with the magnitude of placebo analgesia in pain-free individuals.

BACKGROUND: Task-based functional connectivity (FC) of pain-related regions resulting from expectancy-based placebo induction has yet to be examined, limiting our understanding of regions and networks associated with placebo analgesia. METHODS: Fifty-five healthy pain-free adults over 18 (M = 22.8 years, SD = 7.75) were recruited (65.5% women; 63.6% non-Hispanic/Latino/a/x; 58.2% White). Participants completed a baseline followed by a placebo session involving the topical application of an inactive cream in the context of an expectancy-enhancing instruction set. Noxious heat stimuli were applied to the thenar eminence of the right palm using an fMRI-safe thermode. Stimulus intensity was individually calibrated to produce pain ratings of approximately 40 on a 100-point visual analogue scale. RESULTS: A total of 67.3% of the participants showed a reduction in pain intensity in the placebo condition with an average reduction in pain across the whole sample of 12.7%. Expected pain intensity was associated with reported pain intensity in the placebo session (b = 0.32, p = 0.004, R2 = 0.15). Voxel-wise analyses indicated seven clusters with significant activation during noxious heat stimulation at baseline (pFDR < 0.05). Generalized psychophysiological interaction analysis suggested that placebo-related FC changes between middle frontal gyrus-superior parietal lobule during noxious stimulation were significantly associated with the magnitude of pain reduction (pFDR < 0.05). CONCLUSIONS: Results suggest that stronger expectancy-based placebo responses might be underpinned by greater FC among attentional and somatosensory regions. SIGNIFICANCE: This article provides support and insight for task-dependent functional connectivity differences related to the magnitude of placebo analgesia. Our findings provide key support that the magnitude of expectation-based placebo response depends on the coupling of regions associated with somatosensory and attentional processing.

Expectancy of alcohol analgesia moderates perception of pain relief following acute alcohol intake.

Although laboratory studies indicate alcohol reduces pain intensity and increases pain threshold, these effects likely do not completely explain perceived pain relief from alcohol intake. In this study, we tested expectancy of alcohol analgesia (EAA) as a moderator of subjective pain relief following oral alcohol challenge in individuals with and without chronic orofacial pain. Social drinkers (N = 48; 19 chronic pain; 29 pain-free controls) completed two testing sessions: alcohol administration (BrAC: 0.08 g/dL) and placebo. Alcohol expectancy (AE) was assessed using the EAA questionnaire and two 100-mm Visual Analogue Scales (VASs) regarding strength of belief that alcohol provides pain relief (AE VAS 1) or reduces pain sensitivity (AE VAS 2). Participants completed quantitative sensory testing (QST) involving application of pressure to the masseter insertion. Pain threshold (lbf; three repetitions) and pain intensity (4, 5, and 6 lbf; three repetitions each; 100-mm VAS) were collected. After each stimulus, participants rated perceived pain relief due to consumption of the study beverage (0-100 VAS). Higher EAA and AE VAS 1 ratings were associated with stronger perceived relief in the alcohol, but not placebo, condition. However, expectancy specifically related to reduction in pain sensitivity (AE VAS 2) was not associated with relief. Additionally, changes in pain threshold and intensity were not significantly correlated with perceived relief. Taken together, results suggest expectancy that alcohol provides pain relief is an important determinant of its negative reinforcing effects. Future studies should investigate challenging these expectancies as a means of reducing alcohol-related risk in people with pain. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Pain and alcohol consumption in virtual reality.

Research suggests situational pain may motivate alcohol consumption, suggesting that pain may be an antecedent for problematic drinking behavior. In this pilot project, we assessed the effect of a painful thermal stimulus on drinking topography in a virtual reality bar environment using real alcohol-containing beverages. We also examined psychosocial factors that may account for individual differences in pain as an antecedent for alcohol use. Participants (N = 20, Mage = 25.65 years, 55% female, 15% Hispanic/Latino/a/x) completed a psychosocial screening battery before completing two counterbalanced alcohol self-administration sessions. In each, participants experienced either painful heat (44 °C) or nonnoxious warmth (38 °C). Sip interval (s) and sip volume (g) were measured. Effects of pain on drinking topography were assessed using multilevel models. Multilevel models assessed associations of pain-related changes in topography with hypothesized vulnerability factors. Analyses indicated a significant interaction of pain condition and sex on sip interval (b = -.16.96, p = .015, 95% CI [-30.75, -2.97]), such that painful heat significantly decreased sip interval in men (b = 16.38) but not women (b = -.45). No effect of pain on sip volume was detected (p > .49). Exploratory analyses indicated significant interactions such that the effect of the painful heat condition was stronger in individuals with higher levels of greater negative urgency but the opposite effect for pain catastrophizing. Results suggest acute pain has sex-contingent effects on drinking topography, such that men drank more rapidly while experiencing painful heat. Furthermore, analyses indicated that individuals with greater negative urgency, regardless of sex, may be at elevated risk for hazardous alcohol use when experiencing pain. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Reliability of an adaptive marijuana purchase task.

Purchase tasks are used to measure the value, or demand, for various substances by assessing the amount of a substance individuals would purchase across a series of escalating prices. Marijuana purchase task (MPT) has been previously developed; however, cannabis can be consumed in various forms and measurements, thus raising questions about the applicability of the MPT across cannabis users. An adaptive MPT was developed to allow participants to select their preferred product (e.g., herbal, dabs) and division (e.g., hits, grams). Little research has been done to assess the temporal stability of these measures. Participants (N = 50, Mage = 35.3) who reported at least monthly cannabis use were recruited via Amazon's Mechanical Turk and completed a baseline and repeated original and adaptive MPT. Seventy-two percent (N = 36) of the sample reported the same preferred product and division. Results indicated that the baseline and repeated original MPT were significantly correlated across all indices (rrange = .37-.73), while the baseline and repeated adaptive MPT was significantly correlated with Pmax (r = .31, p = .029) and Omax (r = .57, p < .001). Permutation testing comparing the difference between the original and adaptive MPT on all indices demonstrated a difference for break point (rdifference = .52, p = .004) and elasticity (rdifference = .94, p = .005). Correlations were lower between participants who switched their preferences on the adaptive MPT. Only elasticity was significantly different (rdifference = .93, p = .012) between tasks among participants who did not switch their preferences. Results provide support that both the original and adaptive MPT are reliable across repeated measurement and demonstrate the importance of assessing cannabis product and division preferences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Inspiratory rhythm generation is stabilized by Ih.

Cellular and network properties must be capable of generating rhythmic activity that is both flexible and stable. This is particularly important for breathing, a rhythmic behavior that dynamically adapts to environmental, behavioral, and metabolic changes from the first to the last breath. The pre-Bötzinger complex (preBötC), located within the ventral medulla, is responsible for producing rhythmic inspiration. Its cellular properties must be tunable, flexible as well as stabilizing. Here, we explore the role of the hyperpolarization-activated, nonselective cation current (Ih) for stabilizing PreBötC activity during opioid exposure and reduced excitatory synaptic transmission. Introducing Ih into an in silico preBötC network predicts that loss of this depolarizing current should significantly slow the inspiratory rhythm. By contrast, in vitro and in vivo experiments revealed that the loss of Ih minimally affected breathing frequency, but destabilized rhythmogenesis through the generation of incompletely synchronized bursts (burstlets). Associated with the loss of Ih was an increased susceptibility of breathing to opioid-induced respiratory depression or weakened excitatory synaptic interactions, a paradoxical depolarization at the cellular level, and the suppression of tonic spiking. Tonic spiking activity is generated by nonrhythmic excitatory and inhibitory preBötC neurons, of which a large percentage express Ih. Together, our results suggest that Ih is important for maintaining tonic spiking, stabilizing inspiratory rhythmogenesis, and protecting breathing against perturbations or changes in network state.NEW & NOTEWORTHY The Ih current plays multiple roles within the preBötC. This current is important for promoting intrinsic tonic spiking activity in excitatory and inhibitory neurons and for preserving rhythmic function during conditions that dampen network excitability, such as in the context of opioid-induced respiratory depression. We therefore propose that the Ih current expands the dynamic range of rhythmogenesis, buffers the preBötC against network perturbations, and stabilizes rhythmogenesis by preventing the generation of unsynchronized bursts.

Stress Mediates the Association Between Pain and Alcohol Use in College Students.

Background: Alcohol use in young adults is highly prevalent and associated with numerous consequences, including academic difficulties and motor vehicle accidents. Pain is one factor that has been increasingly shown to be associated with higher rates of alcohol consumption and riskier patterns of drinking among undergraduate students. Although pain has traditionally been viewed as a lesser concern for young adults, current research demonstrates that pain may be more prevalent in younger populations than originally thought. However, little is known about how common psychosocial factors, such as stress and subjective social status (SSS), influence the association between pain and alcohol consumption in college students. Objective: The study's goal was to examine the effect of stress and SSS on the relationship between pain and alcohol consumption. Participants and Methods: Participants (N = 445, 39.3% women, Mage = 22.98) were 18- to 25-year-old college students who completed an online questionnaire. Results: Pain was significantly associated with total weekly alcohol consumption (r(445) = .22, p < 0.001); this association was significantly mediated by stress (b = 0.15, SE = 0.04, 95% CI = [.07,0.23]). SSS was significantly positively associated with alcohol consumption (r(445) = .22, p < 0.001) but was not found to significantly moderate the relationship between stress and alcohol use. Conclusion: Results suggest that efforts to reduce college student alcohol use should include assessment of pain and stress given their association with alcohol consumption. Further, findings suggest that future studies are warranted to prospectively examine pain as an antecedent for alcohol use and to examine the utility of incorporating stress management techniques in pain-focused interventions to indirectly target alcohol use.

A virtual reality platform for the measurement of drinking topography.

BACKGROUND: The assessment of alcohol consumption during a drinking bout, known as drinking topography, may help improve understanding of biopsychosocial mechanisms underlying alcohol consumption. However, past studies have been limited by effort-intensive, time-consuming, and error-prone processes involved in collecting, organizing, and standardizing drinking topography data. Recent technologies allowing integrated data collection and greater environmental control, such as virtual reality (VR), could resolve these problems. METHODS: In this pilot project, we assessed alcohol consumption topography of participants in a VR drinking environment with a programmable virtual confederate (i.e., bar goer) during two testing sessions. In one, the confederate drank quickly (30-60 s sip interval). In the other, the confederate drank slowly (60-120 s sip interval). Participants' hands and beverage were represented in VR. Between sips, beverages were placed on a Bluetooth-enabled scale, allowing real-time updates of drink weight. Participant experience was assessed after each testing visit. Multilevel modeling was used to characterize the effect of confederation condition on sip interval and sip volume. Descriptive analyses were used for participant experience data. RESULTS: Results showed significant, moderate-to-strong between-visit correlations for topographic measures (r = 0.50 to r = 0.84) and indicate participants found the experience to be comfortable and acceptable. Multilevel models indicated participants had greater sip volumes and lower sip intervals when the confederate drank quickly. CONCLUSIONS: Future studies should take advantage of the considerable translational value of this technology to improve understanding of risk associated with individual drinking bouts and develop novel interventions for reducing hazardous drinking.

Dynamic Rhythmogenic Network States Drive Differential Opioid Responses in the In Vitro Respiratory Network.

Death from opioid overdose is typically caused by opioid-induced respiratory depression (OIRD). A particularly dangerous characteristic of OIRD is its apparent unpredictability. The respiratory consequences of opioids can be surprisingly inconsistent, even within the same individual. Despite significant clinical implications, most studies have focused on average dose-r esponses rather than individual variation, and there remains little insight into the etiology of this apparent unpredictability. The preBötzinger complex (preBötC) in the ventral medulla is an important site for generating the respiratory rhythm and OIRD. Here, using male and female C57-Bl6 mice in vitro, we demonstrate that the preBötC can assume different network states depending on the excitability of the preBötC and the intrinsic membrane properties of preBötC neurons. These network states predict the functional consequences of opioids in the preBötC, and depending on network state, respiratory rhythmogenesis can be either stabilized or suppressed by opioids. We hypothesize that the dynamic nature of preBötC rhythmogenic properties, required to endow breathing with remarkable flexibility, also plays a key role in the dangerous unpredictability of OIRD.SIGNIFICANCE STATEMENT Opioids can cause unpredictable, life-threatening suppression of breathing. This apparent unpredictability makes clinical management of opioids difficult while also making it challenging to define the underlying mechanisms of OIRD. Here, we find in brainstem slices that the preBötC, an opioid-sensitive subregion of the brainstem, has an optimal configuration of cellular and network properties that results in a maximally stable breathing rhythm. These properties are dynamic, and the state of each individual preBötC network relative to the optimal configuration of the network predicts how vulnerable rhythmogenesis is to the effects of opioids. These insights establish a framework for understanding how endogenous and exogenous modulation of the rhythmogenic state of the preBötC can increase or decrease the risk of OIRD.

Continuous, multidimensional coding of 3D complex tactile stimuli by primary sensory neurons of the vibrissal system.

Across all sensory modalities, first-stage sensory neurons are an information bottleneck: they must convey all information available for an animal to perceive and act in its environment. Our understanding of coding properties of primary sensory neurons in the auditory and visual systems has been aided by the use of increasingly complex, naturalistic stimulus sets. By comparison, encoding properties of primary somatosensory afferents are poorly understood. Here, we use the rodent whisker system to examine how tactile information is represented in primary sensory neurons of the trigeminal ganglion (Vg). Vg neurons have long been thought to segregate into functional classes associated with separate streams of information processing. However, this view is based on Vg responses to restricted stimulus sets which potentially underreport the coding capabilities of these neurons. In contrast, the current study records Vg responses to complex three-dimensional (3D) stimulation while quantifying the complete 3D whisker shape and mechanics, thereby beginning to reveal their full representational capabilities. The results show that individual Vg neurons simultaneously represent multiple mechanical features of a stimulus, do not preferentially encode principal components of the stimuli, and represent continuous and tiled variations of all available mechanical information. These results directly contrast with proposed codes in which subpopulations of Vg neurons encode select stimulus features. Instead, individual Vg neurons likely overcome the information bottleneck by encoding large regions of a complex sensory space. This proposed tiled and multidimensional representation at the Vg directly constrains the computations performed by more central neurons of the vibrissotrigeminal pathway.

The effect of next day responsibilities and an adaptive purchase task on cannabis demand.

BACKGROUND: The marijuana purchase task (MPT) is a commonly used behavioral economic measure of relative cannabis value (i.e. demand) that presents specific methodological concerns due to non-standardized measurement, variability in modality of use, and evolving legalization policies. Refinement of the task is critical to improve task ecological validity and accurate measurement of cannabis demand. The present study examined the construct validity of an adaptive MPT that allowed for participant selection of their preferred cannabis-based product and unit of measurement and the effect of next-day responsibilities on demand. METHODS: Participants reporting at least monthly cannabis use (N = 186, 40.3 % women, Mage = 33.59) were recruited via Amazon Mechanical Turk and completed the original MPT and our adaptive form with 2 next-day responsibilities scenarios (no responsibilities vs. morning job interview) for each MPT. Cannabis use motives, problems, and risk for cannabis use disorder were also assessed. RESULTS: Cannabis demand was sensitive to next-day responsibility, with higher hypothetical consumption observed in the no responsibilities condition. Responsibility-related decreases in Omax (F(1,185) = 4.83, p = .029, η2p = .03) were significantly greater on the adaptive MPT than the original MPT. Demand indices derived from the adaptive MPT were significantly correlated with cannabis problems (rbreakpoint = .19, rPmax = 0.18, relasticity=-0.18) and motives (rrange=-.32-.25), and demand metrics from the original MPT. CONCLUSIONS: Results provide preliminary support for the construct validity of an adaptive MPT and suggest that early-morning work responsibilities may reduce cannabis demand. Continued research is needed to further refine this task and determine implications for cannabis use disorder intervention and prevention approaches.

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network.

The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the µ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBötzinger Complex (preBötC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBötC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: (1) pre-inspiratory spiking is reduced and (2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.

A dynamical model for generating synthetic data to quantify active tactile sensing behavior in the rat.

As it becomes possible to simulate increasingly complex neural networks, it becomes correspondingly important to model the sensory information that animals actively acquire: the biomechanics of sensory acquisition directly determines the sensory input and therefore neural processing. Here, we exploit the tractable mechanics of the well-studied rodent vibrissal ("whisker") system to present a model that can simulate the signals acquired by a full sensor array actively sampling the environment. Rodents actively "whisk" ∼60 vibrissae (whiskers) to obtain tactile information, and this system is therefore ideal to study closed-loop sensorimotor processing. The simulation framework presented here, WHISKiT Physics, incorporates realistic morphology of the rat whisker array to predict the time-varying mechanical signals generated at each whisker base during sensory acquisition. Single-whisker dynamics were optimized based on experimental data and then validated against free tip oscillations and dynamic responses to collisions. The model is then extrapolated to include all whiskers in the array, incorporating each whisker's individual geometry. Simulation examples in laboratory and natural environments demonstrate that WHISKiT Physics can predict input signals during various behaviors, currently impossible in the biological animal. In one exemplary use of the model, the results suggest that active whisking increases in-plane whisker bending compared to passive stimulation and that principal component analysis can reveal the relative contributions of whisker identity and mechanics at each whisker base to the vibrissotactile response. These results highlight how interactions between array morphology and individual whisker geometry and dynamics shape the signals that the brain must process.

Associations of Regional and Network Functional Connectivity With Exercise-Induced Low Back Pain.

Musculoskeletal pain is an aversive experience that exists within a variety of conditions and can result in significant impairment for individuals. Gaining greater understanding of the factors related to pain vulnerability and resilience to musculoskeletal pain may help target at-risk individuals for early intervention. This analysis builds on our previous work identifying regions where greater gray matter density was associated with lower pain following standardized, exercise induced musculoskeletal injury. Here we sought to examine the relationship between baseline resting state functional connectivity in a priori regions and networks, and delayed onset muscle soreness (DOMS) pain intensity following a single session of eccentric exercise in healthy adults. Participants completed a baseline functional MRI scan and a high intensity trunk exercise protocol in the erector spinae. Pain intensity ratings were collected 48-hours later. Resting state functional connectivity from four seed regions and 3 networks were separately regressed on pain intensity scores. Results revealed that connectivity between left middle frontal gyrus, the left occipital gyrus and cerebellar network seeds and clusters associated with discriminative, emotional, and cognitive aspects of pain were associated with lower post-DOMS pain. Results suggest resilience to clinically relevant pain is associated with aspects of regional and network neural coherence. Investigations of pain modulatory capacity that integrate multimodal neuroimaging metrics are called for. PERSPECTIVE: Our results provide key support for the role of structural and functional coherence in regional and network connectivity in adaptive pain response and represent an important step in clarifying neural mechanisms of resilience to clinically relevant pain.