The Sensitivity of Limited-Sequence MRI in Identifying Pediatric Cervical Spine Injury: A Western Pediatric Surgery Research Consortium Multicenter Retrospective Cohort Study.

INTRODUCTION: Clinical clearance of a child's cervical spine after trauma is often challenging due to impaired mental status or an unreliable neurologic examination. Magnetic resonance imaging (MRI) is the gold standard for excluding ligamentous injury in children but is constrained by long image acquisition times and frequent need for anesthesia. Limited-sequence MRI (LSMRI) is used in evaluating the evolution of traumatic brain injury and may also be useful for cervical spine clearance while potentially avoiding the need for anesthesia. The purpose of this study was to assess the sensitivity and negative predictive value of LSMRI as compared to gold standard full-sequence MRI as a screening tool to rule out clinically significant ligamentous cervical spine injury. METHODS: We conducted a ten-center, five-year retrospective cohort study (2017-2021) of all children (0-18y) with a cervical spine MRI after blunt trauma. MRI images were re-reviewed by a study pediatric radiologist at each site to determine if the presence of an injury could be identified on limited sequences alone. Unstable cervical spine injury was determined by study neurosurgeon review at each site. RESULTS: We identified 2,663 children less than 18 years of age who underwent an MRI of the cervical spine with 1,008 injuries detected on full-sequence studies. The sensitivity and negative predictive value of LSMRI were both >99% for detecting any injury and 100% for detecting any unstable injury. Young children (age < 5 years) were more likely to be electively intubated or sedated for cervical spine MRI. CONCLUSION: LSMRI is reliably detects clinically significant ligamentous injury in children after blunt trauma. To decrease anesthesia use and minimize MRI time, trauma centers should develop LSMRI screening protocols for children without a reliable neurologic exam. LEVEL OF EVIDENCE: 2 (Diagnostic Tests or Criteria).

The insula in nicotine use disorder: Functional neuroimaging and implications for neuromodulation.

Insula dysfunction contributes to nicotine use disorders. Yet, much remains unknown about how insular functions promote nicotine use. We review current models of brain networks in smoking and propose an extension to those models that emphasizes the role of the insula in craving. During acute withdrawal, the insula provides the sensation of craving to the cerebrum and is thought to negotiate craving sensations with cognitive control to guide behavior - either to smoke or abstain. Recent studies have shown that insula processing is saturable, such that different insular functions compete for limited resources. We propose that this saturability explains how craving during withdrawal can overload insular processing to the exclusion of other functions, such as saliency and network homeostasis. A novel signal flow model illustrates how limited insular capacity leads to breakdown of normal function. Finally, we discuss suitability of insula as a neuromodulation target to promote cessation. Given the limited efficacy of standard-of-care treatments for nicotine use disorder, insular neuromodulation offers an innovative, potentially therapeutic target for improving smoking cessation.

Neuroimaging reward, craving, learning, and cognitive control in substance use disorders: review and implications for treatment.

Substance use disorder is a leading causes of preventable disease and mortality. Drugs of abuse cause molecular and cellular changes in specific brain regions and these neuroplastic changes are thought to play a role in the transition to uncontrolled drug use. Neuroimaging has identified neural substrates associated with problematic substance use and may offer clues to reduce its burden on the patient and society. Here, we provide a narrative review of neuroimaging studies that have examined the structures and circuits associated with reward, cues and craving, learning, and cognitive control in substance use disorders. Most studies use advanced MRI or positron emission tomography (PET). Many studies have focused on the dopamine neurons of the ventral tegmental area, and the regions where these neurons terminate, such as the striatum and prefrontal cortex. Decreases in dopamine receptors and transmission have been found in chronic users of drugs, alcohol, and nicotine. Recent studies also show evidence of differences in structure and function in substance users relative to controls in brain regions involved in salience evaluation, such as the insula and anterior cingulate cortex. Balancing between reward-related bottom-up and cognitive-control-related top-down processes is discussed in the context of neuromodulation as a potential treatment. Finally, some of the challenges for understanding substance use disorder using neuroimaging methods are discussed.

Behavioral approach and orbitofrontal cortical activity during decision-making in substance dependence.

Behavioral approach, defined as behavior directed toward a reward or novel stimulus, when elevated, may increase one's vulnerability to substance use disorder. Behavioral approach has been associated with relatively greater left compared to right frontal activity; behavioral inhibition may be associated with relatively greater right compared to left frontal brain activity. We hypothesized that substance dependent individuals (SDI) would have higher behavioral approach than controls and greater prefrontal cortical activity during decision-making involving reward. We hypothesized that behavioral approach would correlate with left frontal activity during decision-making and that the correlation would be stronger in SDI than controls. 31 SDI and 21 controls completed the Behavioral Inhibition System/Behavioral Approach System (BIS/BAS) scales and performed a decision-making task during fMRI. Orbitofrontal (OFC) and dorsolateral prefrontal activity were correlated with BIS and BAS scores. Compared to controls, SDI had higher BAS Fun Seeking scores (p<0.001) and worse decision-making performance (p=0.004). BAS Fun Seeking correlated with left OFC activity during decision-making across group (r=0.444, p<0.003). The correlation did not differ by group. There was no correlation between BIS and right frontal activity. Left OFC may play a role in reward-related decision-making in substance use disorder especially in individuals with high behavioral approach.

Imaging decision about whether to benefit self by harming others: Adolescents with conduct and substance problems, with or without callous-unemotionality, or developing typically.

We sought to identify brain activation differences in conduct-problem youth with limited prosocial emotions (LPE) compared to conduct-problem youth without LPE and community adolescents, and to test associations between brain activation and severity of callous-unemotional traits. We utilized a novel task, which asks subjects to repeatedly decide whether to accept offers where they will benefit but a beneficent other will be harmed. Behavior on this task has been previously associated with levels of prosocial emotions and severity of callous-unemotional traits, and is related to empathic concern. During fMRI acquisition, 66 male adolescents (21 conduct-problem patients with LPE, 21 without, and 24 typically-developing controls) played this novel game. Within typically-developing controls, we identified a network engaged during decision involving bilateral insula, and inferior parietal and medial frontal cortices, among other regions. Group comparisons using non-parametric (distribution-free) permutation tests demonstrated LPE patients had lower activation estimates than typically-developing adolescents in right anterior insula. Additional significant group differences emerged with our a priori parametric cluster-wise inference threshold. These results suggest measurable functional brain activation differences in conduct-problem adolescents with LPE compared to typically-developing adolescents. Such differences may underscore differential treatment needs for conduct-problem males with and without LPE.

Sex disparities in substance abuse research: Evaluating 23 years of structural neuroimaging studies.

BACKGROUND: Sex differences in brain structure and clinical course of substance use disorders underscores the need to include women in structural brain imaging studies. The NIH has supported the need for research to address sex differences. We evaluated female enrollment in substance abuse structural brain imaging research and the methods used to study sex differences in substance effects. METHODS: Structural brain imaging studies published through 2016 (n=230) were evaluated for number of participants by sex and substance use status and methods used to evaluate sex differences. Temporal trends in the numbers of participants by sex and substance use status were analyzed. We evaluated how often sex effects were appropriately analyzed and the proportion of studies that found sex by substance interactions on volumetric measures. RESULTS: Female enrollment increased over time, but remained significantly lower than male enrollment (p=0.01), with the greatest bias for alcohol and opiate studies. 79% of studies included both sexes; however, 74% did not evaluate sex effects or used an analytic approach that precluded detection of sex by substance use interactions. 85% of studies that stratified by sex reported different substance effects on brain volumes. Only 33% of studies examining two-way interactions found significant interactions, highlighting that many studies were underpowered to detect interactions. CONCLUSIONS: Although female participation in substance use studies of brain morphometry has increased, sex disparity persists. Studying adequate numbers of both sexes and employing correct analytic approaches is critical for understanding sex differences in brain morphometric changes in substance abuse.

Top-Down Network Effective Connectivity in Abstinent Substance Dependent Individuals.

OBJECTIVE: We hypothesized that compared to healthy controls, long-term abstinent substance dependent individuals (SDI) will differ in their effective connectivity between large-scale brain networks and demonstrate increased directional information from executive control to interoception-, reward-, and habit-related networks. In addition, using graph theory to compare network efficiencies we predicted decreased small-worldness in SDI compared to controls. METHODS: 50 SDI and 50 controls of similar sex and age completed psychological surveys and resting state fMRI. fMRI results were analyzed using group independent component analysis; 14 networks-of-interest (NOI) were selected using template matching to a canonical set of resting state networks. The number, direction, and strength of connections between NOI were analyzed with Granger Causality. Within-group thresholds were p<0.005 using a bootstrap permutation. Between group thresholds were p<0.05, FDR-corrected for multiple comparisons. NOI were correlated with behavioral measures, and group-level graph theory measures were compared. RESULTS: Compared to controls, SDI showed significantly greater Granger causal connectivity from right executive control network (RECN) to dorsal default mode network (dDMN) and from dDMN to basal ganglia network (BGN). RECN was negatively correlated with impulsivity, behavioral approach, and negative affect; dDMN was positively correlated with impulsivity. Among the 14 NOI, SDI showed greater bidirectional connectivity; controls showed more unidirectional connectivity. SDI demonstrated greater global efficiency and lower local efficiency. CONCLUSIONS: Increased effective connectivity in long-term abstinent drug users may reflect improved cognitive control over habit and reward processes. Higher global and lower local efficiency across all networks in SDI compared to controls may reflect connectivity changes associated with drug dependence or remission and requires future, longitudinal studies to confirm.

Sex Differences in Gray Matter Changes and Brain-Behavior Relationships in Patients with Stimulant Dependence.

PURPOSE: To investigate whether sex modulates the effects of stimulant dependence on gray matter volume (GMV) in patients who have achieved long-term abstinence and to characterize how sex modulates GMV according to specific behavioral measures, such as dependence symptom count, behavioral approach, and impulsivity. MATERIALS AND METHODS: Colorado Multiple Institutional Review Board approval and informed consent were obtained. In this prospective parallel group study, 127 age- and sex-matched participants (68 control subjects [28 women, 40 men] and 59 patients with stimulant dependence [28 women, 31 men]) underwent T1-weighted spoiled gradient-echo inversion recovery magnetic resonance imaging of the brain at 3 T. Images were segmented by using voxel-based morphometric software. After adjustment for age, education, and head size, the effects of group according to sex on GMV and main effects were analyzed throughout the whole brain by using an analysis of covariance family-wise cluster corrected for multiple comparisons, with a threshold P value of less than .05. Dependence symptom count and behavioral measurements were correlated with GMV in the whole brain and in five a priori regions of interest. RESULTS: The effects of group according to sex on GMV were significant in numerous regions (P < .001). Compared with female control subjects, women with stimulant dependence had significantly lower GMV in widespread brain regions (P < .001). There were no significant differences in GMV between male control subjects and men with stimulant dependence (P = .625). Dependence symptom count negatively correlated with GMV in the nucleus accumbens in women (left: r = -0.364, P = .047; right: r = -0.407, P = .031) but not in men (left: r = -0.063, P = .737; right: r = -0.174, P = .349). Behavioral approach (P = .002) and impulsivity (P = .013) correlated negatively with frontal and temporal GMV changes in women with stimulant dependence but not in the other groups. CONCLUSION: Vast changes in GMV were observed in women with stimulant dependence after prolonged abstinence, but were not observed in men. Sexual dimorphism in drug-related neuroanatomic changes and brain-behavior relationships may be mechanisms underlying the difference in clinical profiles of addiction between women and men.

Female adolescents with severe substance and conduct problems have substantially less brain gray matter volume.

OBJECTIVE: Structural neuroimaging studies have demonstrated lower regional gray matter volume in adolescents with severe substance and conduct problems. These research studies, including ours, have generally focused on male-only or mixed-sex samples of adolescents with conduct and/or substance problems. Here we compare gray matter volume between female adolescents with severe substance and conduct problems and female healthy controls of similar ages. HYPOTHESES: Female adolescents with severe substance and conduct problems will show significantly less gray matter volume in frontal regions critical to inhibition (i.e. dorsolateral prefrontal cortex and ventrolateral prefrontal cortex), conflict processing (i.e., anterior cingulate), valuation of expected outcomes (i.e., medial orbitofrontal cortex) and the dopamine reward system (i.e. striatum). METHODS: We conducted whole-brain voxel-based morphometric comparison of structural MR images of 22 patients (14-18 years) with severe substance and conduct problems and 21 controls of similar age using statistical parametric mapping (SPM) and voxel-based morphometric (VBM8) toolbox. We tested group differences in regional gray matter volume with analyses of covariance, adjusting for age and IQ at p<0.05, corrected for multiple comparisons at whole-brain cluster-level threshold. RESULTS: Female adolescents with severe substance and conduct problems compared to controls showed significantly less gray matter volume in right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex, medial orbitofrontal cortex, anterior cingulate, bilateral somatosensory cortex, left supramarginal gyrus, and bilateral angular gyrus. Considering the entire brain, patients had 9.5% less overall gray matter volume compared to controls. CONCLUSIONS: Female adolescents with severe substance and conduct problems in comparison to similarly aged female healthy controls showed substantially lower gray matter volume in brain regions involved in inhibition, conflict processing, valuation of outcomes, decision-making, reward, risk-taking, and rule-breaking antisocial behavior.

Influence of dorsolateral prefrontal cortex and ventral striatum on risk avoidance in addiction: a mediation analysis.

BACKGROUND: Alterations in frontal and striatal function are hypothesized to underlie risky decision making in drug users, but how these regions interact to affect behavior is incompletely understood. We used mediation analysis to investigate how prefrontal cortex and ventral striatum together influence risk avoidance in abstinent drug users. METHOD: Thirty-seven abstinent substance-dependent individuals (SDI) and 43 controls underwent fMRI while performing a decision-making task involving risk and reward. Analyses of a priori regions-of-interest tested whether activity in dorsolateral prefrontal cortex (DLPFC) and ventral striatum (VST) explained group differences in risk avoidance. Whole-brain analysis was conducted to identify brain regions influencing the negative VST-risk avoidance relationship. RESULTS: Right DLPFC (RDLPFC) positively mediated the group-risk avoidance relationship (p < 0.05); RDLPFC activity was higher in SDI and predicted higher risk avoidance across groups, controlling for SDI vs. CONTROLS: Conversely, VST activity negatively influenced risk avoidance (p < 0.05); it was higher in SDI, and predicted lower risk avoidance. Whole-brain analysis revealed that, across group, RDLPFC and left temporal-parietal junction positively (p ≤ 0.001) while right thalamus and left middle frontal gyrus negatively (p < 0.005) mediated the VST activity-risk avoidance relationship. CONCLUSION: RDLPFC activity mediated less risky decision making while VST mediated more risky decision making across drug users and controls. These results suggest a dual pathway underlying decision making, which, if imbalanced, may adversely influence choices involving risk. Modeling contributions of multiple brain systems to behavior through mediation analysis could lead to a better understanding of mechanisms of behavior and suggest neuromodulatory treatments for addiction.

Characterizing the relationship between functional MRI-derived measures and clinical outcomes in patients with vascular lesions.

OBJECT: Functional MRI (fMRI) has proven to be an effective component of pretreatment planning in patients harboring a variety of different brain lesions. The authors have recently reported significant relationships concerning distances between brain tumor borders and areas of functional activation (lesion-to-activation distance; LAD) with regard to patient morbidity and mortality. This study further examines the relationship between LAD, focusing on a host of vascular lesions and pre- and posttreatment morbidity. METHODS: This study included a sample population of patients with vascular lesions (n = 106), primarily arteriovenous malformations (AVMs) and cavernomas. These patients underwent pretreatment fMRI-based motor mapping (n = 72) or language mapping (n = 84). The impact of LAD and other variables derived from the patient medical record were analyzed with respect to functional deficits in terms of morbidity (weakness and/or aphasia). RESULTS: In patients with no pretreatment deficits, there was trend for a significant relationship between the Wernicke area LAD and posttreatment language deficits. In patients with or without pretreatment deficits, a trend toward significance was observed between sensorimotor LAD and posttreatment motor deficits. Additionally, lesion type (AVMs or cavernomas) affected posttreatment deficits, with more patients with cavernomas showing posttreatment language deficits than patients with AVMs. However, this difference was not observed for posttreatment motor deficits. CONCLUSIONS: These findings suggest that the proximity of a vascular lesion to sensorimotor and language areas is a relevant parameter in estimating patient prognosis in the perioperative period. Additionally, vascular lesion type and existence of pretreatment deficits play a significant role in outcomes.

The distribution of vestibular efferent neurons receiving innervation of secondary vestibular afferent nerves in rats.

OBJECTIVES/HYPOTHESIS: To explore the innervation areas of the medial vestibular nucleus (MVN) afferent neurons onto vestibular efferent neurons in the brain stem of rats. STUDY DESIGN: A morphology study in the central vestibular system. METHODS: Two neuronal tracers were used. Lectin PHA-L Conjugates (PHA-L, Invitrogen L - 11270,) was injected into the MVN as an anterograde tracer, and 5% FluoSpheres carboxylate-modified microspheres (MFS, Molecular Probe F-8793) was injected into the contralateral peripheral vestibule using as a retrograde tracer. All animals were allowed to recover for 12 days to facilitate sufficient transportation of the tracers. Then brain stems were sliced coronally on a freezing microtome and observed under a fluorescence microscope and laser confocal microscopy. RESULTS: Neurons in the MVN labeled with PHA-L exhibited green fluorescence, and their axons were distributed near the genu of the facial nerve (g7) and in the reticulation structure, as well as in the cerebellum or oculomotor-related nuclei. Neurons labeled with red fluorescence of MFS were mainly located dorsomedial and dorsolateral to g7 and in the caudal pontine reticular nucleus (PnC) bilaterally and presented different morphologies at different locations. The synaptic junctions would display color overlap (fluoresced yellow). Under three-dimensional reconstruction of the confocal laser microscopy, the synaptic junctions were visualized dorsomedial and dorsolateral to g7 bilaterally, predominantly ipsilateral to the MVN injection site. CONCLUSIONS: Morphologic evidence of the distribution of vestibular efferent neurons synapsed by afferent nerves from MVN was demonstrated. These efferent neurons constitute short closed-loop circuits with neurons in the MVN.

The effect of vocal fold adduction on the acoustic quality of phonation: ex vivo investigations.

OBJECTIVES: The purpose of this study was to investigate the effect of vocal fold adduction on voice quality in an ex vivo larynx model. STUDY DESIGN: Prospective, repeated-measures experiments. METHODS: Ten excised canine larynges were mounted on an excised larynx phonation system and measurements were recorded for three different vocal fold adduction levels. Acoustic perturbation measurements of jitter, shimmer, and signal-to-noise ratio (SNR) were calculated from recorded radiated sound histories. RESULTS: Ex vivo experiments indicated that statistically significant increases in the means of jitter (P=0.005), shimmer (P=0.002), and SNR (P=0.011) measures decreased with respect to vocal fold adduction as the independent variable. Theoretical results showed that the direct current (DC) and alternating current (AC) component of glottal area increased monotonically with prephonatory glottal area. CONCLUSIONS: Acoustic perturbation increased with the degree of vocal fold abduction. Ex vivo larynx measurements suggested that a hyperadducted state may be acoustically best. This may be explained theoretically by an increase in DC/AC ratio as the prephonatory area is increased.

Effects of surface dehydration on mucosal wave amplitude and frequency in excised canine larynges.

OBJECTIVE: Evaluate the effect of vocal fold surface dehydration on mucosal wave amplitude and frequency. STUDY DESIGN: Controlled test-retest. SETTING: Larynges were mounted on an excised larynx phonation system and attached to a pseudolung in a triple-walled sound-attenuated room that eliminated background noise and maintained a stabilized room temperature and humidity level. SUBJECTS AND METHODS: High-speed video was recorded for 8 excised canine larynges during exposure to dehumidified air at 20 cm H(2)O. Control trials consisted of high-speed videos recorded for 2 excised canine larynges during exposure to humidified air at the same pressure. RESULTS: In the majority of larynges, increased levels of dehydration were correlated with decreased amplitude and frequency. The slope of the linear regression fitted to the change in amplitude (P = .003) and the percent change (P < .001) between the initial and final trials were significantly decreased in dehydrated larynges. These measurements with respect to the change in frequency were also significantly decreased in dehydrated larynges (P < .001; P = .027). CONCLUSION: Vocal fold surface dehydration caused a decrease in mucosal wave amplitude and frequency. This study provides objective, quantitative support for the mechanism of voice deterioration observed after extreme surface dehydration.

Correlative study of indirect computed tomography lymphography using iopamidol and histopathology in a cervical lymph node metastasis model.

OBJECTIVES/HYPOTHESIS: To investigate the potential usefulness of indirect computed tomography lymphography (CT-LG) with iopamidol in the detection of cervical lymph node metastases in a VX2 rabbit tongue cancer model. STUDY DESIGN: Randomized controlled trial. METHODS: Thirty-seven rabbits were randomly divided into control (n = 7) and tongue tumor-bearing (n = 30) groups. In the control group, indirect CT-LG was performed with 0.5- and 0.25-mL injections of iopamidol in the right and left tongue submucosa, respectively. In the tumor-bearing group, indirect CT-LG with 0.5 mL of iopamidol was performed on day 11 (n = 8), 14 (n = 8), 21 (n = 8), or 28 (n = 6) after carcinoma transplant. The correlation between indirect CT-LG and histopathology was investigated. RESULTS: In normal rabbits, oval or round enhanced cervical lymph nodes in each side of the neck were visualized by indirect CT-LG. In tumor-bearing rabbits, one enhanced lymph node on each side of the neck was visualized with or without filling defects in all rabbits except two on day 28 in which lymph nodes were not enhanced. The sensitivity, specificity, accuracy, and positive and negative predictive values for using filling defects on CT-LG as a diagnostic criterion were 77.4%, 77.8%, 77.6%, 80%, and 75%, respectively. Indirect CT-LG detected 84.6% of 2- to 6-mm intranodal tumor deposits. CONCLUSIONS: Indirect CT-LG may be useful for differentiating metastatic from nonmetastatic lymph nodes.

Theoretical modeling and experimental high-speed imaging of elongated vocal folds.

In this paper, the role of vocal fold elongation in governing glottal movement dynamics was theoretically and experimentally investigated. A theoretical model was first proposed to incorporate vocal fold elongation into the two-mass model. This model predicted the direct and nondirect components of the glottal time series as a function of vocal fold elongation. Furthermore, high-speed digital imaging was applied in excised larynx experiments to visualize vocal fold vibrations with variable vocal fold elongation from -10% to 50% and subglottal pressures of 18- and 24-cm H(2)O. Comparison between theoretical model simulations and experimental observations showed good agreement. A relative maximum was seen in the nondirect component of glottal area, suggesting that an optimal elongation could maximize the vocal fold vibratory power. However, sufficiently large vocal fold elongations caused the nondirect component to approach zero and the direct component to approach a constant. These results showed that vocal fold elongation plays an important role in governing the dynamics of glottal area movement and validated the applicability of the proposed theoretical model and high-speed imaging to investigate laryngeal activity.

Phonation threshold power in ex vivo laryngeal models.

This study hypothesized that phonation threshold power is measureable and sensitive to changes in the biomechanical properties of the vocal folds. Phonation threshold power was measured in three sample populations of 10 excised canine larynges treated with variable posterior glottal gap, variable bilateral vocal fold elongation, and variable vocal fold lesioning. Posterior glottal gap varied from 0 to 4mm in 0.5 mm intervals. Bilateral vocal fold elongation varied from 0% to 20% in 5% intervals. Vocal fold lesion treatments included unilateral and bilateral vocal fold lesion groups. Each treatment was investigated independently in a sample population of 10 excised canine larynges. Linear regression analysis indicated that phonation threshold power was sensitive to posterior glottal gap (R2=0.298, P<0.001) and weakly to vocal fold elongation (R2=0.052, P=0.003). A one-way repeated measures analysis of variance indicated that phonation threshold power was sensitive to the presence of lesions (P<0.001). Theoretical and experimental evidence presented here suggests that phonation threshold power could be used as a broad screening parameter sensitive to certain changes in the biomechanical properties of the larynx. It has not yet been measured in humans, but because it has the potential to represent the airflow-tissue energy transfer more completely than the phonation threshold pressure or flow alone, it may be a more useful parameter than these and could be used to indicate that laryngeal health is likely abnormal.