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Introduction:Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, ca

Topical anesthetic and distraction are effective pain management techniques, yet they have not been fully evaluated for infants. Eighty-four 1-year-olds undergoing immunizations were randomized to distraction, topical anesthetic, or control. The 42 infants who returned for their 18-month injections were evaluated for long-term treatment gains. An observational scale revealed that infants demonstrated lower distress with distraction than topical anesthetic or control during the recovery phase of the injection at 12 months, and parents and nurses rated infants as more distressed at 12 than 18 months. Distress measures were positively associated across time. [ABSTRACT FROM AUTHOR]

Growing interest in promoting cross-disciplinary collaboration among health scientists has prompted several federal agencies, including the NIH, to establish large, multicenter initiatives intended to foster collaborative research and training. In order to assess whether these initiatives are effective in promoting scientific collaboration that ultimately results in public health improvements, it is necessary to develop new strategies for evaluating research processes and products as well as the longer-term societal outcomes associated with these programs. Ideally, evaluative measures should be administered over the entire course of large initiatives, including their near-term and later phases. The present study focuses on the development of new tools for assessing the readiness for collaboration among health scientists at the outset (during the first year) of their participation in the National Cancer Institute's Transdisciplinary Research on Energetics and Cancer (TREC) initiative. Indexes of collaborative readiness, along with additional measures of near-term collaborative processes, were administered as part of the TREC Year-One evaluation survey. Additionally, early progress toward scientific collaboration and integration was assessed, using a protocol for evaluating written research products. Results from the Year-One survey and the ratings of written products provide evidence of cross-disciplinary collaboration among participants during the first year of the initiative, and also reveal opportunities for enhancing collaborative processes and outcomes during subsequent phases of the project. The implications of these findings for future evaluations of team science initiatives are discussed. [ABSTRACT FROM AUTHOR]

Background: Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status., Methods: The authors implemented a battery of behavioral tests in mice of both sexes that received (1) no injury; (2) an incision model of postoperative pain; (3) a spared nerve injury model of neuropathic pain; and (4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays., Results: The authors report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors, and aversion. Both conditional deletion and pharmacologic blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion., Conclusions: The authors conclude that Y2 at central terminals of primary afferent neurons provides tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Pain and itch are regulated by a diverse array of neuropeptides and their receptors in superficial laminae of the spinal cord dorsal horn (DH). Neuropeptide Y (NPY) is normally expressed on DH neurons but not sensory neurons. By contrast, the Npy2r receptor (Y2) is expressed on the central and peripheral terminals of sensory neurons but not on DH neurons. Neurophysiological slice recordings indicate that Y2-selective agonists inhibits spinal neurotransmitter release from sensory neurons. However, behavioral pharmacology studies indicate that Y2 agonists exert minimal changes in nociception, even after injury. Additional discrepancies in the behavioral actions of the Y2-antagonist BIIE0246 - reports of either pronociception or antinociception - have now been resolved. In the normal state, spinally-directed (intrathecal) administration of BIIE0246 elicits ongoing nociception, hypersensitivity to sensory stimulation, and aversion. Conversely, in the setting of nerve injury and inflammation, intrathecal BIIE024 reduced not only mechanical and thermal hypersensitivity, but also a measure of the affective dimension of pain (conditioned place preference). When administered in chronic pain models of latent sensitization, BIIE0246 produced a profound reinstatement of pain-like behaviors. We propose that tissue or nerve injury induces a G protein switch in the action of NPY-Y2 signaling from antinociception in the naïve state to the inhibition of mechanical and heat hyperalgesia in the injured state, and then a switch back to antinociception to keep LS in a state of remission. This model clarifies the pharmacotherapeutic potential of Y2 research, pointing to the development of a new non-opioid pharmacotherapy for chronic pain using Y2 antagonists in patients who do not develop LS., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Pediatric obesity rates have quadrupled in the United States, and deficits in higher-order cognition have been linked to obesity, though it remains poorly understood how deviations from normal body mass are related to the neural dynamics serving cognition in youth. Herein, we determine how age- and sex-adjusted measures of body mass index (zBMI) scale with neural activity in brain regions underlying fluid intelligence. Seventy-two youth aged 9-16 years underwent high-density magnetoencephalography while performing an abstract reasoning task. The resulting data were transformed into the time-frequency domain and significant oscillatory responses were imaged using a beamformer. Whole-brain correlations with zBMI were subsequently conducted to quantify relationships between zBMI and neural activity serving abstract reasoning. Our results reveal that participants with higher zBMI exhibit attenuated theta (4-8 Hz) responses in both the left dorsolateral prefrontal cortex and left temporoparietal junction, and that weaker temporoparietal responses scale with slower reaction times. These findings suggest that higher zBMI values are associated with weaker theta oscillations in key brain regions and altered performance during an abstract reasoning task. Thus, future investigations should evaluate neurobehavioral function during abstract reasoning in youth with more severe obesity to identify the potential impact., (© 2024. The Author(s).)

Emotional intelligence includes an assortment of factors related to emotion function. Such factors involve emotion recognition (in this case via facial expression), emotion trait, reactivity, and regulation. We aimed to investigate how the subjective appraisals of emotional intelligence (i.e. trait, reactivity, and regulation) are associated with objective emotion recognition accuracy, and how these associations differ between young and older adults. Data were extracted from the CamCAN dataset (189 adults: 57 young/118 older) from assessments measuring these emotion constructs. Using linear regression models, we found that greater negative reactivity was associated with better emotion recognition accuracy among older adults, though the pattern was opposite for young adults with the greatest difference in disgust and surprise recognition. Positive reactivity and depression level predicted surprise recognition, with the associations significantly differing between the age groups. The present findings suggest the level to which older and young adults react to emotional stimuli differentially predicts their ability to correctly identify facial emotion expressions. Older adults with higher negative reactivity may be able to integrate their negative emotions effectively in order to recognize other's negative emotions more accurately. Alternatively, young adults may experience interference from negative reactivity, lowering their ability to recognize other's negative emotions.

The altered sensorimotor cortical dynamics seen in youth with cerebral palsy appear to be tightly coupled with their motor performance errors and uncharacteristic mobility. Very few investigations have used these cortical dynamics as potential biomarkers to predict the extent of the motor performance changes that might be seen after physical therapy or in the design of new therapeutic interventions that target a youth's specific neurophysiological deficits. This cohort investigation was directed at evaluating the practice dependent changes in the sensorimotor cortical oscillations exhibited by youth with cerebral palsy as a step towards addressing this gap. We used magnetoencephalography to image the changes in the cortical oscillations before and after youth with cerebral palsy ( N = 25; age = 15.2 ± 4.5 years; Gross Motor Function Classification Score Levels I-III) and neurotypical controls ( N = 18; age = 14.6 ± 3.1 years) practiced a knee extension isometric target-matching task. Subsequently, structural equation modelling was used to assess the multivariate relationship between changes in beta (16-22 Hz) and gamma (66-82 Hz) oscillations and the motor performance after practice. The structural equation modelling results suggested youth with cerebral palsy who had a faster reaction time after practice tended to also have a stronger peri-movement beta oscillation in the sensorimotor cortices following practicing. The stronger beta oscillations were inferred to reflect greater certainty in the selected motor plan. The models also indicated that youth with cerebral palsy who overshot the targets less and matched the targets sooner tended to have a stronger execution-related gamma response in the sensorimotor cortices after practice. This stronger gamma response may represent improve activation of the sensorimotor neural generators and/or alterations in the GABAergic interneuron inhibitory-excitatory dynamics. These novel neurophysiological results provide a window on the potential neurological changes governing the practice-related outcomes in the context of the physical therapy., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The refinement of brain morphology extends across childhood, and exposure to environmental toxins during this period may alter typical trends. Radon is a highly common radiologic toxin with a well-established role in cancer among adults. However, effects on developmental populations are understudied in comparison. This study investigated whether home radon exposure is associated with altered brain morphology in youths. Fifty-four participants (6-14 yrs, M=10.52 yrs, 48.15% male, 89% White) completed a T1-weighted MRI and home measures of radon. We observed a significant multivariate effect of home radon concentrations, which was driven by effects on GMV. Specifically, higher home radon was associated with smaller GMV (F=6.800, p=.012, η p 2 =.13). Conversely, there was a trending radon-by-age interaction on WMV, which reached significance when accounting for the chronicity of radon exposure (F=4.12, p=.049, η p 2 =.09). We found that youths with above-average radon exposure showed no change in WMV with age, whereas low radon was linked with normative, age-related WMV increases. These results suggest that everyday home radon exposure may alter sensitive structural brain development, impacting developmental trajectories in both gray and white matter., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brittany K Taylor reports financial support was provided by National Institute of Environmental Health Sciences. Tony W Wilson reports financial support was provided by National Institute of Mental Health. Brittany K Taylor reports financial support was provided by National Institute of General Medical Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Surface-feeding aquatic animals navigate towards the source of water disturbances and must differentiate prey from other environmental stimuli. Medicinal leeches locate prey, in part, using a distribution of mechanosensory hairs along their body that deflect under fluid flow. Leech's behavioral responses to surface wave temporal frequency are well documented. However, a surface wave's temporal frequency depends on many underlying environmental and fluid properties that vary substantially in natural habitats (e.g., water depth, temperature). The impact of these variables on neural response and behavior is unknown. Here, we developed a physics-based leech mechanosensor model to examine the impact of environmental and fluid properties on neural response. Our model used the physical properties of a leech cilium and was verified against existing behavioral and electrophysiological data. The model's peak response occurred with waves where the effects of gravity and surface tension were nearly equal (i.e., the phase velocity minimum). This suggests that preferred stimuli are related to the interaction between fundamental properties of the surrounding medium and the mechanical properties of the sensor. This interaction likely tunes the sensor to detect the nondispersive components of the signal, filtering out irrelevant ambient stimuli, and may be a general property of cilia across the animal kingdom., Competing Interests: Declaration of competing interest None, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Radon is a naturally occurring gas that contributes significantly to radiation in the environment and is the second leading cause of lung cancer globally. Previous studies have shown that other environmental toxins have deleterious effects on brain development, though radon has not been studied as thoroughly in this context. This study examined the impact of home radon exposure on the neural oscillatory activity serving attention reorientation in youths. Fifty-six participants (ages 6-14 years) completed a classic Posner cuing task during magnetoencephalography (MEG), and home radon levels were measured for each participant. Time-frequency spectrograms indicated stronger theta (3-7 Hz, 300-800 ms), alpha (9-13 Hz, 400-900 ms), and beta responses (14-24 Hz, 400-900 ms) during the task relative to baseline. Source reconstruction of each significant oscillatory response was performed, and validity maps were computed by subtracting the task conditions (invalidly cued - validly cued). These validity maps were examined for associations with radon exposure, age, and their interaction in a linear regression design. Children with greater radon exposure showed aberrant oscillatory activity across distributed regions critical for attentional processing and attention reorientation (e.g., dorsolateral prefrontal cortex, and anterior cingulate cortex). Generally, youths with greater radon exposure exhibited a reverse neural validity effect in almost all regions and showed greater overall power relative to peers with lesser radon exposure. We also detected an interactive effect between radon exposure and age where youths with greater radon exposure exhibited divergent developmental trajectories in neural substrates implicated in attentional processing (e.g., bilateral prefrontal cortices, superior temporal gyri, and inferior parietal lobules). These data suggest aberrant, but potentially compensatory neural processing as a function of increasing home radon exposure in areas critical for attention and higher order cognition., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Throughout childhood and adolescence, the brain undergoes significant structural and functional changes that contribute to the maturation of multiple cognitive domains, including selective attention. Selective attention is crucial for healthy executive functioning and while key brain regions serving selective attention have been identified, their age-related changes in neural oscillatory dynamics and connectivity remain largely unknown. We examined the developmental sensitivity of selective attention circuitry in 91 typically developing youth aged 6 - 13 years old. Participants completed a number-based Simon task while undergoing magnetoencephalography (MEG) and the resulting data were preprocessed and transformed into the time-frequency domain. Significant oscillatory brain responses were imaged using a beamforming approach, and task-related peak voxels in the occipital, parietal, and cerebellar cortices were used as seeds for subsequent whole-brain connectivity analyses in the alpha and gamma range. Our key findings revealed developmentally sensitive connectivity profiles in multiple regions crucial for selective attention, including the temporoparietal junction (alpha) and prefrontal cortex (gamma). Overall, these findings suggest that brain regions serving selective attention are highly sensitive to developmental changes during the pubertal transition period., Competing Interests: Declaration of Competing Interest All authors report no biomedical financial interests or potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Certain animal species use the Earth's magnetic field (i.e. magnetoreception) alongside their other sensory modalities to navigate long distances that include continents and oceans. It is hypothesized that several animals use geomagnetic parameters, such as field intensity and inclination, to recognize specific locations or regions, potentially enabling migration without a pre-surveyed map. However, it is unknown how animals use geomagnetic information to generate guidance commands, or where in the world this type of strategy would maximize an animal's fitness. While animal experiments have been invaluable in advancing this area, the phenomenon is difficult to study in vivo or in situ , especially on the global scale where the spatial layout of the geomagnetic field is not constant. Alongside empirical animal experiments, mathematical modeling and simulation are complementary tools that can be used to investigate animal navigation on a global scale, providing insights that can be informative across a number of species. In this study, we present a model in which a simulated animal (i.e. agent) navigates via an algorithm which determines travel heading based on local and goal magnetic signatures (here, combinations of geomagnetic intensity and inclination) in a realistic model of Earth's magnetic field. By varying parameters of the navigation algorithm, different regions of the world can be made more or less reliable to navigate. We present a mathematical analysis of the system. Our results show that certain regions can be navigated effectively using this strategy when these parameters are properly tuned, while other regions may require more complex navigational strategies. In a real animal, parameters such as these could be tuned by evolution for successful navigation in the animal's natural range. These results could also help with developing engineered navigation systems that are less reliant on satellite-based methods., (Creative Commons Attribution license.)

Introduction: It is well-established that chronic exposure to environmental toxins can have adverse effects on neuropsychological health, particularly in developing youths. However, home radon, a ubiquitous radiotoxin, has been seldom studied in this context. In the present study, we investigated the degree to which chronic everyday home radon exposure was associated with alterations in transdiagnostic mental health outcomes., Methods: A total of 59 children and adolescents ages 6- to 14-years-old ( M  = 10.47 years, SD  = 2.58; 28 males) completed the study. Parents completed questionnaires detailing aspects of attention and executive function. We used a principal components analysis to derive three domains of neuropsychological functioning: 1) task-based executive function skills, 2) self-and emotion-regulation abilities, and 3) inhibitory control. Additionally, parents completed a home radon test kit and provided information on how long their child had lived in the tested home. We computed a radon exposure index per person based on the duration of time that the child had lived in the home and their measured home radon concentration. Youths were divided into terciles based on their radon exposure index score. Using a MANCOVA design, we determined whether there were differences in neuropsychological domain scores across the three groups, controlling for age, sex, and socioeconomic status., Results: There was a significant multivariate effect of radon group on neuropsychological dysfunction (λ = 0.77, F  = 2.32, p  = 0.038, η p 2  = 0.12). Examination of univariate effects revealed specific increases in self-and emotion-regulation dysfunction among the youths with the greatest degree of chronic home radon exposure ( F  = 7.21, p  = 0.002, η p 2  = 0.21). There were no significant differences by group in the other tested domains., Discussion: The data suggest potential specificity in the neurotoxic effects of everyday home radon exposure in developing youths, with significant aberrations in self-and emotion-regulation faculties. These findings support the need for better public awareness and public health policy surrounding home radon safety and mitigation strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Taylor, Pulliam, Smith, Rice, Johnson, Coutant, Glesinger and Wilson.)

Even in the modern era of combination antiretroviral therapy, aberrations in motor control remain a predominant symptom contributing to age-related functional dependencies (e.g., neurocognitive impairment) in people with HIV (PWH). While recent evidence implicates aberrant mitochondrial redox environments in the modulation of neural oscillatory activity serving motor control in PWH, the contribution of important clinical and demographic factors on this bioenergetic-neural-behavioral pathway is unknown. Herein, we evaluate the predictive capacity of clinical metrics pertinent to HIV (e.g., CD4 nadir, time with viremia) and age on mitochondrial redox-regulated sensorimotor brain-behavior dynamics in 69 virally-suppressed PWH. We used state-of-the-art systems biology and neuroscience approaches, including Seahorse analyzer of mitochondrial energetics, EPR spectroscopy of intracellular oxidant levels, antioxidant activity assays pertinent to superoxide and hydrogen peroxide (H 2 O 2 ) redox environments, and magnetoencephalographic (MEG) imaging to quantify sensorimotor oscillatory dynamics. Our results demonstrate differential effects of redox systems on the neural dynamics serving motor function in PWH. In addition, measures of immune stability and duration of compromise due to HIV had dissociable effects on this pathway, above and beyond the effects of age alone. Moreover, peripheral measures of antioxidant activity (i.e., superoxide dismutase) fully mediated the relationship between immune stability and current behavioral performance, indicative of persistent oxidative environments serving motor control in the presence of virologic suppression. Taken together, our data suggest that disease-related factors, in particular, are stronger predictors of current redox, neural and behavioral profiles serving motor function, which may serve as effective targets for alleviating HIV-specific alterations in cognitive-motor function in the future., Competing Interests: Declarations of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Emerging evidence indicates that aberrations in sensorimotor cortical oscillations likely play a key role in uncharacteristic motor actions seen in cerebral palsy. This interpretation is largely centered on the assumption that the aberrant cortical oscillations primarily reflect the motor aspects, with less consideration of possible higher-order cognitive connections. To directly probe this view, we examined the impact of cognitive interference on the sensorimotor cortical oscillations seen in persons with cerebral palsy using magnetoencephalography. Persons with cerebral palsy (N = 26, 9-47 years old) and controls (N = 46, 11-49 years) underwent magnetoencephalographic imaging while completing an arrow-based version of the Eriksen flanker task. Structural equation modeling was used to evaluate the relationship between the extent of interference generated by the flanker task and the strength of the sensorimotor cortical oscillations and motor performance. Our results indicated that the impact of cognitive interference on beta and gamma oscillations moderated the interference effect on reaction times in persons with cerebral palsy, above and beyond that seen in controls. Overall, these findings suggest that alterations in sensorimotor oscillatory activity in those with cerebral palsy at least partly reflects top-down control influences on the motor system. Thus, suppression of distracting stimuli should be a consideration when evaluating altered motor actions in cerebral palsy., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background: Psychosocial distress among youth is a major public health issue characterized by disruptions in cognitive control processing. Using the National Institute of Mental Health's Research Domain Criteria (RDoC) framework, we quantified multidimensional neural oscillatory markers of psychosocial distress serving cognitive control in youth., Methods: The sample consisted of 39 peri-adolescent participants who completed the NIH Toolbox Emotion Battery (NIHTB-EB) and the Eriksen flanker task during magnetoencephalography (MEG). A psychosocial distress index was computed with exploratory factor analysis using assessments from the NIHTB-EB. MEG data were analyzed in the time-frequency domain and peak voxels from oscillatory maps depicting the neural cognitive interference effect were extracted for voxel time series analyses to identify spontaneous and oscillatory aberrations in dynamics serving cognitive control as a function of psychosocial distress. Further, we quantified the relationship between psychosocial distress and dynamic functional connectivity between regions supporting cognitive control., Results: The continuous psychosocial distress index was strongly associated with validated measures of pediatric psychopathology. Theta-band neural cognitive interference was identified in the left dorsolateral prefrontal cortex (dlPFC) and middle cingulate cortex (MCC). Time series analyses of these regions indicated that greater psychosocial distress was associated with elevated spontaneous activity in both the dlPFC and MCC and blunted theta oscillations in the MCC. Finally, we found that stronger phase coherence between the dlPFC and MCC was associated with greater psychosocial distress., Conclusions: Greater psychosocial distress was marked by alterations in spontaneous and oscillatory theta activity serving cognitive control, along with hyperconnectivity between the dlPFC and MCC., Competing Interests: The authors report no biomedical financial interests or potential conflicts of interest., (© 2023 The Authors.)

The transition from childhood to adolescence is associated with an influx of sex hormones, which not only facilitates physical and behavioral changes, but also dramatic changes in neural circuitry. While previous work has shown that pubertal hormones modulate structural and functional brain development, few of these studies have focused on the impact that such hormones have on spontaneous cortical activity, and whether these effects are modulated by sex during this critical developmental window. Herein, we examined the effect of endogenous testosterone on spontaneous cortical activity in 71 typically-developing youth (ages 10-17 years; 32 male). Participants completed a resting-state magnetoencephalographic (MEG) recording, structural MRI, and provided a saliva sample for hormone analysis. MEG data were source-reconstructed and the power within five canonical frequency bands (delta, theta, alpha, beta, and gamma) was computed. The resulting power spectral density maps were analyzed via vertex-wise ANCOVAs to identify spatially specific effects of testosterone and sex by testosterone interactions, while covarying out age. We found robust sex differences in the modulatory effects of testosterone on spontaneous delta, beta, and gamma activity. These interactions were largely confined to frontal cortices and exhibited a stark switch in the directionality of the correlation from the low (delta) to high frequencies (beta/gamma). For example, in the delta band, greater testosterone related to lower relative power in prefrontal cortices in boys, while the reverse pattern was found for girls. These data suggest testosterone levels are uniquely related to the development of spontaneous cortical dynamics during adolescence, and such levels are associated with different developmental patterns in males and females within regions implicated in executive functioning., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Intersectional genetics have yielded tremendous advances in our understanding of molecularly identified subpopulations and circuits within the dorsal horn in neuropathic pain. The authors tested the hypothesis that spinal µ opioid receptor-expressing neurons (Oprm1-expressing neurons) contribute to behavioral hypersensitivity and neuronal sensitization in the spared nerve injury model in mice., Methods: The authors coupled the use of Oprm1Cre transgenic reporter mice with whole cell patch clamp electrophysiology in lumbar spinal cord slices to evaluate the neuronal activity of Oprm1-expressing neurons in the spared nerve injury model of neuropathic pain. The authors used a chemogenetic approach to activate or inhibit Oprm1-expressing neurons, followed by the assessment of behavioral signs of neuropathic pain., Results: The authors reveal that spared nerve injury yielded a robust neuroplasticity of Oprm1-expressing neurons. Spared nerve injury reduced Oprm1 gene expression in the dorsal horn as well as the responsiveness of Oprm1-expressing neurons to the selective µ agonist (D-Ala2, N-MePhe4, Gly-ol)-enkephalin (DAMGO). Spared nerve injury sensitized Oprm1-expressing neurons, as reflected by an increase in their intrinsic excitability (rheobase, sham 38.62 ± 25.87 pA [n = 29]; spared nerve injury, 18.33 ± 10.29 pA [n = 29], P = 0.0026) and spontaneous synaptic activity (spontaneous excitatory postsynaptic current frequency in delayed firing neurons: sham, 0.81 ± 0.67 Hz [n = 14]; spared nerve injury, 1.74 ± 1.68 Hz [n = 10], P = 0.0466), and light brush-induced coexpression of the immediate early gene product, Fos in laminae I to II (%Fos/tdTomato+: sham, 0.42 ± 0.57% [n = 3]; spared nerve injury, 28.26 ± 1.92% [n = 3], P = 0.0001). Chemogenetic activation of Oprm1-expressing neurons produced mechanical hypersensitivity in uninjured mice (saline, 2.91 ± 1.08 g [n = 6]; clozapine N-oxide, 0.65 ± 0.34 g [n = 6], P = 0.0006), while chemogenetic inhibition reduced behavioral signs of mechanical hypersensitivity (saline, 0.38 ± 0.37 g [n = 6]; clozapine N-oxide, 1.05 ± 0.42 g [n = 6], P = 0.0052) and cold hypersensitivity (saline, 6.89 ± 0.88 s [n = 5] vs. clozapine N-oxide, 2.31 ± 0.52 s [n = 5], P = 0.0017)., Conclusions: The authors conclude that nerve injury sensitizes pronociceptive µ opioid receptor-expressing neurons in mouse dorsal horn. Nonopioid strategies to inhibit these interneurons might yield new treatments for neuropathic pain., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Neuropeptide Y targets the Y1 receptor (Y1) in the spinal dorsal horn (DH) to produce endogenous and exogenous analgesia. DH interneurons that express Y1 (Y1-INs; encoded by Npy1r) are necessary and sufficient for neuropathic hypersensitivity after peripheral nerve injury. However, as Y1-INs are heterogenous in composition in terms of morphology, neurophysiological characteristics, and gene expression, we hypothesized that a more precisely defined subpopulation mediates neuropathic hypersensitivity. Using fluorescence in situ hybridization, we found that Y1-INs segregate into 3 largely nonoverlapping subpopulations defined by the coexpression of Npy1r with gastrin-releasing peptide (Grp/Npy1r), neuropeptide FF (Npff/Npy1r), and cholecystokinin (Cck/Npy1r) in the superficial DH of mice, nonhuman primates, and humans. Next, we analyzed the functional significance of Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r INs to neuropathic pain using a mouse model of peripheral nerve injury. We found that chemogenetic inhibition of Npff/Npy1r-INs did not change the behavioral signs of neuropathic pain. Further, inhibition of Y1-INs with an intrathecal Y1 agonist, [Leu31, Pro34]-NPY, reduced neuropathic hypersensitivity in mice with conditional deletion of Npy1r from CCK-INs and NPFF-INs but not from GRP-INs. We conclude that Grp/Npy1r-INs are conserved in higher order mammalian species and represent a promising and precise pharmacotherapeutic target for the treatment of neuropathic pain.

Background: A myocardial ischemia/reperfusion (IR) injury activates the transient receptor potential vanilloid 1 (TRPV1) dorsal root ganglion (DRG) neurons. The activation of TRPV1 DRG neurons triggers the spinal dorsal horn and the sympathetic preganglionic neurons in the spinal intermediolateral column, which results in sympathoexcitation. In this study, we hypothesize that the selective epidural administration of resiniferatoxin (RTX) to DRGs may provide cardioprotection against ventricular arrhythmias by inhibiting afferent neurotransmission during IR injury., Methods: Yorkshire pigs ( n = 21) were assigned to either the sham, IR, or IR + RTX group. A laminectomy and sternotomy were performed on the anesthetized animals to expose the left T2-T4 spinal dorsal root and the heart for IR intervention, respectively. RTX (50 μg) was administered to the DRGs in the IR + RTX group. The activation recovery interval (ARI) was measured as a surrogate for the action potential duration (APD). Arrhythmia risk was investigated by assessing the dispersion of repolarization (DOR), a marker of arrhythmogenicity, and measuring the arrhythmia score and the number of non-sustained ventricular tachycardias (VTs). TRPV1 and calcitonin gene-related peptide (CGRP) expressions in DRGs and CGRP expression in the spinal cord were assessed using immunohistochemistry., Results: The RTX mitigated IR-induced ARI shortening (-105 ms ± 13 ms in IR vs. -65 ms ± 11 ms in IR + RTX, p = 0.028) and DOR augmentation (7093 ms 2 ± 701 ms 2 in IR vs. 3788 ms 2 ± 1161 ms 2 in IR + RTX, p = 0.020). The arrhythmia score and VT episodes during an IR were decreased by RTX (arrhythmia score: 8.01 ± 1.44 in IR vs. 3.70 ± 0.81 in IR + RTX, p = 0.037. number of VT episodes: 12.00 ± 3.29 in IR vs. 0.57 ± 0.3 in IR + RTX, p = 0.002). The CGRP expression in the DRGs and spinal cord was decreased by RTX (DRGs: 6.8% ± 1.3% in IR vs. 0.6% ± 0.2% in IR + RTX, p < 0.001. Spinal cord: 12.0% ± 2.6% in IR vs. 4.5% ± 0.8% in IR + RTX, p = 0.047)., Conclusions: The administration of RTX locally to thoracic DRGs reduces ventricular arrhythmia in a porcine model of IR, likely by inhibiting spinal afferent hyperactivity in the cardio-spinal sympathetic pathways.

The neural and cognitive processes underlying the flexible allocation of attention undergo a protracted developmental course with changes occurring throughout adolescence. Despite documented age-related improvements in attentional reorienting throughout childhood and adolescence, the neural correlates underlying such changes in reorienting remain unclear. Herein, we used magnetoencephalography (MEG) to examine neural dynamics during a Posner attention-reorienting task in 80 healthy youth (6-14 years old). The MEG data were examined in the time-frequency domain and significant oscillatory responses were imaged in anatomical space. During the reorienting of attention, youth recruited a distributed network of regions in the fronto-parietal network, along with higher-order visual regions within the theta (3-7 Hz) and alpha-beta (10-24 Hz) spectral windows. Beyond the expected developmental improvements in behavioral performance, we found stronger theta oscillatory activity as a function of age across a network of prefrontal brain regions irrespective of condition, as well as more limited age- and validity-related effects for alpha-beta responses. Distinct brain-behavior associations between theta oscillations and attention-related symptomology were also uncovered across a network of brain regions. Taken together, these data are the first to demonstrate developmental effects in the spectrally-specific neural oscillations serving the flexible allocation of attention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Over the past decade, transdiagnostic indicators in relation to neurobiological processes have provided extensive insight into youth's risk for psychopathology. During development, exposure to childhood trauma and dysregulation (i.e., so-called AAA symptomology: anxiety, aggression, and attention problems) puts individuals at a disproportionate risk for developing psychopathology and altered network-level neural functioning. Evidence for the latter has emerged from resting-state fMRI studies linking mental health symptoms and aberrations in functional networks (e.g., cognitive control (CCN), default mode networks (DMN)) in youth, although few of these investigations have used longitudinal designs. Herein, we leveraged a three-year longitudinal study to identify whether traumatic exposures and concomitant dysregulation trigger changes in the developmental trajectories of resting-state functional networks involved in cognitive control ( N = 190; 91 females; time 1 M age = 11.81). Findings from latent growth curve analyses revealed that greater trauma exposure predicted increasing connectivity between the CCN and DMN across time. Greater levels of dysregulation predicted reductions in within-network connectivity in the CCN. These findings presented in typically developing youth corroborate connectivity patterns reported in clinical populations, suggesting there is predictive utility in using transdiagnostic indicators to forecast alterations in resting-state networks implicated in psychopathology.

Tissue injury creates a delicate balance between latent pain sensitization (LS) and compensatory endogenous analgesia. Inhibitory G-protein-coupled receptor (GPCR) interactions that oppose LS, including μ-opioid receptor (MOR) or neuropeptide Y Y1 receptor (Y1R) activity, persist in the spinal cord dorsal horn (DH) for months, even after the resolution of normal pain thresholds. Here, we demonstrate that following recovery from surgical incision, a potent endogenous analgesic synergy between MOR and Y1R activity persists within DH interneurons to reduce the intensity and duration of latent postoperative hypersensitivity and ongoing pain. Failure of such endogenous GPCR signaling to maintain LS in remission may underlie the transition from acute to chronic pain states., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

Approximately half of patients with alcohol use disorder report pain and this can be severe during withdrawal. Many questions remain regarding the importance of biological sex, alcohol exposure paradigm, and stimulus modality to the severity of alcohol withdrawal-induced hyperalgesia. To examine the impact of sex and blood alcohol concentration on the time course of the development of mechanical and heat hyperalgesia, we characterized a mouse model of chronic alcohol withdrawal-induced pain in the presence or absence the alcohol dehydrogenase inhibitor, pyrazole. Male and female C57BL/6J mice underwent chronic intermittent ethanol vapor ± pyrazole exposure for 4 weeks, 4 d/wk to induce ethanol dependence. Hind paw sensitivity to the plantar application of mechanical (von Frey filaments) and radiant heat stimuli were measured during weekly observations at 1, 3, 5, 7, 24, and 48 hours after cessation of ethanol exposure. In the presence of pyrazole, males developed mechanical hyperalgesia after the first week of chronic intermittent ethanol vapor exposure, peaking at 48 hours after cessation of ethanol. By contrast, females did not develop mechanical hyperalgesia until the fourth week; this also required pyrazole and did not peak until 48 hours. Heat hyperalgesia was consistently observed only in females exposed to ethanol and pyrazole; this developed after the first weekly session and peaked at 1 hour. We conclude that Chronic alcohol withdrawal-induced pain develops in a sex-, time-, and blood alcohol concentration-dependent manner in C57BL/6J mice. PERSPECTIVE: Alcohol withdrawal-induced pain is a debilitating condition in individuals with AUD. Our study found mice experience alcohol withdrawal-induced pain in a sex and time course specific manor. These findings will aid in elucidating mechanisms of chronic pain and AUD and will help individuals remain abstinent from alcohol., (Copyright © 2023. Published by Elsevier Inc.)