Impact of a Collaborative Radiology Utilization Management Program: Does the Specialty of the Referring Provider Matter?

OBJECTIVE: The purpose of this study was to evaluate the impact of a collaborative radiology utilization management program on the disposition of cases according to provider specialty. MATERIALS AND METHODS: A utilization management program directed by a radiology benefit management company provided peer-to-peer decision support for providers ordering advanced outpatient imaging studies. After a radiologist reviewed the cases, based upon provider specialty, the rates of the following dispositions were analyzed: study approved by consensus, study changed by consensus, study not performed by consensus, study approved (no consensus), and study administratively not performed (no callback). Aggregated rates of study changed or not performed by consensus (withdrawals) were used to assess the effect of provider-radiologist collaboration. The rate of no callback was used to assess sentinel effect. The combined rate of withdrawals and no callback represented the overall impact of radiologist participation. The project period was 5 years. RESULTS: A total of 168,915 studies were reviewed: 58.6% were approved, 6.8% were changed, and 13.5% were withdrawn by consensus; 6.0% were approved without consensus; 15.2% were withdrawn because of no callback; 35.5% initially ordered were not performed at the time they were ordered. Family practice (25.3%) and internal medicine (23.8%) had the highest aggregated rates of study changed or withdrawn by consensus. Thoracic surgery (13.3%), neurosurgery (11.2%), and orthopedic surgery (9.3%) had the lowest rates. Internal medicine (18.0%), neurology (17.7%), and family practice (17.4%) had the highest rates of study withdrawn owing to no callback. Pediatrics (7.1%) and ophthalmology (7.3%) had the lowest rates. The overall impact was greatest for family practice (42.7%), internal medicine (41.8%), and neurology (33.4%) and least for orthopedic surgery (22.8%) and neurosurgery (24.0%). CONCLUSION: Radiologist participation had substantial impact regardless of provider specialty. The impact was greatest on primary care providers who are heavier users of radiology.

The effects of chronic alcohol self-administration in nonhuman primate brain networks.

BACKGROUND: Long-term alcohol abuse is associated with change in behavior, brain structure, and brain function. However, the nature of these changes is not well understood. In this study, we used network science to analyze a nonhuman primate model of ethanol self-administration to evaluate functional differences between animals with chronic alcohol use and animals with no exposure to alcohol. Of particular interest was how chronic alcohol exposure may affect the resting state network. METHODS: Baseline resting state functional magnetic resonance imaging was acquired in a cohort of vervet monkeys. Animals underwent an induction period where they were exposed to an isocaloric maltose dextrin solution (control) or ethanol in escalating doses over three 30-day epochs. Following induction, animals were given ad libitum access to water and a maltose dextrin solution (control) or water and ethanol for 22 h/d over 12 months. Cross-sectional analyses examined region of interests in hubs and community structure across animals to determine differences between drinking and nondrinking animals after the 12-month free access period. RESULTS: Animals were classified as lighter (<2.0 g/kg/d) or heavier drinkers (≥2.0 g/kg/d) based on a median split of their intake pattern during the 12-month ethanol free access period. Statistical analysis of hub connectivity showed significant differences in heavier drinkers for hubs in the precuneus, posterior parietal cortices, superior temporal gyrus, subgenual cingulate, and sensorimotor cortex. Heavier drinkers were also shown to have less consistent communities across the brain compared to lighter drinkers. The different level of consumption between the lighter and heavier drinking monkeys suggests that differences in connectivity may be intake dependent. CONCLUSIONS: Animals that consume alcohol show topological differences in brain network organization, particularly in animals that drink heavily. Differences in the resting state network were linked to areas that are associated with spatial association, working memory, and visuomotor processing.

Monkey alcohol tissue research resource: banking tissues for alcohol research.

BACKGROUND: An estimated 18 million adults in the United States meet the clinical criteria for diagnosis of alcohol abuse or alcoholism, a disorder ranked as the third leading cause of preventable death. In addition to brain pathology, heavy alcohol consumption is comorbid with damage to major organs including heart, lungs, liver, pancreas, and kidneys. Much of what is known about risk for and consequences of heavy consumption derive from rodent or retrospective human studies. The neurobiological effects of chronic intake in rodent studies may not easily translate to humans due to key differences in brain structure and organization between species, including a lack of higher-order cognitive functions, and differences in underlying prefrontal cortical neural structures that characterize the primate brain. Further, rodents do not voluntarily consume large quantities of ethanol (EtOH) and they metabolize it more rapidly than primates. METHODS: The basis of the Monkey Alcohol Tissue Research Resource (MATRR) is that nonhuman primates, specifically monkeys, show a range of drinking excessive amounts of alcohol (>3.0 g/kg or a 12 drink equivalent per day) over long periods of time (12 to 30 months) with concomitant pathological changes in endocrine, hepatic, and central nervous system (CNS) processes. The patterns and range of alcohol intake that monkeys voluntarily consume parallel what is observed in humans with alcohol use disorders and the longitudinal experimental design spans stages of drinking from the EtOH-naïve state to early exposure through chronic abuse. Age- and sex-matched control animals self-administer an isocaloric solution under identical operant procedures. RESULTS: The MATRR is a unique postmortem tissue bank that provides CNS and peripheral tissues, and associated bioinformatics from monkeys that self-administer EtOH using a standardized experimental paradigm to the broader alcohol research community. CONCLUSIONS: This resource provides a translational platform from which we can better understand the disease processes associated with alcoholism.

Standardized method for the harvest of nonhuman primate tissue optimized for multiple modes of analyses.

Appropriate animal models are critical to conduct translational studies of human disorders without variables that can confound clinical studies. Such analytic methods as patch-clamp electrophysiological and voltammetric recordings of neurons in brain slices require living brain tissue. In order to obtain viable tissue from nonhuman primate brains, tissue collection methods must be designed to preserve cardiovascular and respiratory functions for as long as possible. This paper describes a method of necropsy that has been used in three species of monkeys that satisfies this requirement. At necropsy, animals were maintained under a deep surgical plane of anesthesia while a craniotomy was conducted to expose the brain. Following the craniotomy, animals were perfused with ice-cold, oxygenated artificial cerebrospinal fluid to displace blood and to reduce the temperature of the entire brain. The brain was removed within minutes of death and specific brain regions were immediately dissected for subsequent in vitro electrophysiology or voltammetry experiments. This necropsy method also provided for the collection of tissue blocks containing all brain regions that were immediately frozen and stored for subsequent genomic, proteomic, autoradiographic and histological studies. An added benefit from the design of this necropsy method is that all major peripheral tissues were also collected and are now being utilized in a wide range of genomic, biochemical and histological assays. This necropsy method has resulted in the establishment and growth of a nonhuman primate alcohol tissue bank designed to distribute central nervous system and peripheral tissues to the larger scientific community.

The signature of maternal rearing in the methylome in rhesus macaque prefrontal cortex and T cells.

Early-life adversity is associated with a broad scope of life-long health and behavioral disorders. Particularly critical is the role of the mother. A possible mechanism is that these effects are mediated by "epigenetic" mechanisms. Studies in rodents suggest a causal relationship between early-life adversity and changes in DNA methylation in several "candidate genes" in the brain. This study examines whether randomized differential rearing (maternal vs surrogate-peer rearing) of rhesus macaques is associated with differential methylation in early adulthood. The data presented here show that differential rearing leads to differential DNA methylation in both prefrontal cortex and T cells. These differentially methylated promoters tend to cluster by both chromosomal region and gene function. The broad impact of maternal rearing on DNA methylation in both the brain and T cells supports the hypothesis that the response to early-life adversity is system-wide and genome-wide and persists to adulthood. Our data also point to the feasibility of studying the impact of the social environment in peripheral T-cell DNA methylation.

The effects of alcohol on the nonhuman primate brain: a network science approach to neuroimaging.

BACKGROUND: Animal studies have long been an important tool for basic research as they offer a degree of control often lacking in clinical studies. Of particular value is the use of nonhuman primates (NHPs) for neuroimaging studies. Currently, studies have been published using functional magnetic resonance imaging (fMRI) to understand the default-mode network in the NHP brain. Network science provides an alternative approach to neuroimaging allowing for evaluation of whole-brain connectivity. In this study, we used network science to build NHP brain networks from fMRI data to understand the basic functional organization of the NHP brain. We also explored how the brain network is affected following an acute ethanol (EtOH) pharmacological challenge. METHODS: Baseline resting-state fMRI was acquired in an adult male rhesus macaque (n = 1) and a cohort of vervet monkeys (n = 10). A follow-up scan was conducted in the rhesus macaque to assess network variability and to assess the effects of an acute EtOH challenge on the brain network. RESULTS: The most connected regions in the resting-state networks were similar across species and matched regions identified as the default-mode network in previous NHP fMRI studies. Under an acute EtOH challenge, the functional organization of the brain was significantly impacted. CONCLUSIONS: Network science offers a great opportunity to understand the brain as a complex system and how pharmacological conditions can affect the system globally. These models are sensitive to changes in the brain and may prove to be a valuable tool in long-term studies on alcohol exposure.

Long-term effects of differential early rearing in rhesus macaques: behavioral reactivity in adulthood.

Adverse early experiences are associated with a range of deleterious health outcomes in humans, including higher risk for affective disorders. Studies using a long-standing model of nonhuman primate model of early adversity have demonstrated that nursery-reared (NR) monkeys exhibit alterations in multiple aspects of biobehavioral development; however, few studies have evaluated the persistence of socioaffective behavioral changes through adulthood. We evaluated the effects of early rearing experience on adult animals' response to a well-validated assessment of anxiety-like behavior, the human intruder paradigm (HIP). We tested 22 rhesus monkeys who were either nursery-reared (NR) or reared with their mothers (mother-reared; MR). NR monkeys were inhibited in their behavior compared to MR monkeys, with reduced locomotion and exploratory behaviors. NR animals showed a marginal increase in freezing. Together these findings demonstrate that the consequences of differential infant rearing experience on socioaffective behavior persist into adulthood, with evidence of greater inhibition in NR monkeys.

The association between a history of anxiety or depression and utilization of diagnostic imaging.

OBJECTIVE: While prior research shows that mental illness is associated with lower utilization of screening imaging, little is known about how mental illness impacts use of diagnostic imaging, other than for screening. This study explores the association between a history of anxiety or depression in the prior year and utilization of diagnostic imaging. METHODS: Commercial and Medicare Advantage health plan claims from 2017 and 2018 from patients with plans from one national organization were extracted. Exclusions were made for patients without continuous plan enrollment. History of anxiety or depression was determined using 2017 claims, and downstream diagnostic imaging was determined using 2018 claims. Univariate associations were assessed with Chi-square tests. A matched sample was created using Coarsened Exact Matching, with history of mental illness serving as the treatment variable. Logistic regressions were used to calculate adjusted odds ratios, before and after matching, controlling for age, sex, urbanicity, local income, comorbidities, claims history, region, and health plan characteristics. Associations between mental illness and chest imaging, neuroimaging, and emergency department imaging were also evaluated. RESULTS: The sample included 2,381,851 patients before matching. Imaging was significantly more likely for patients with a history of anxiety (71.1% vs. 55.7%, P < .001) and depression (73.2% vs. 55.3%, P < .001). The adjusted odds of any imaging were 1.24 (95% confidence interval [CI]: 1.22-1.26) for patients with a history of anxiety, and 1.43 (CI: 1.41-1.45) for patients with a history of depression before matching, and 1.18 (CI: 1.16-1.20) for a history of anxiety and 1.33 (CI: 1.32-1.35) for a history of depression after matching. Adjusted analyses found significant, positive associations between mental illness and chest imaging, neuroimaging, and emergency department imaging both before and after matching. DISCUSSION: In contrast to prior findings on screening, anxiety and depression were associated with greater likelihood of diagnostic imaging within the population studied.

Up-regulation and functional effect of cardiac ß3-adrenoreceptors in alcoholic monkeys.

BACKGROUND: Recent studies link altered cardiac beta-adrenergic receptor (AR) signaling to the pathology of alcoholic cardiomyopathy (ACM). However, the alteration and functional effect of beta(3)-AR activation in ACM are unknown. We tested the hypothesis that chronic alcohol intake causes an up-regulation of cardiac beta(3)-AR, which exacerbates myocyte dysfunction and impairs calcium regulation, thereby directly contributing to the progression of ACM. METHODS: We compared myocyte beta(3)- and beta(1)-AR expression and myocyte contractile ([Ca(2+)](i)), transient ([Ca(2+)](iT)), and Ca(2+) current (I(Ca,L)) responses to beta- and beta(3)-AR stimulation in myocytes obtained from left ventricle (LV) tissue samples obtained from 10 normal control (C) and 16 monkeys with self-administered alcohol for 12 months prior to necropsy: 6 moderate (M) and 10 heavy (H) drinkers with group average alcohol intakes of 1.5 +/- 0.2 and 3.3 +/- 0.2 g/kg/d, respectively. RESULTS: Compared with control myocytes (C), in alcoholic cardiomyocytes, basal cell contraction (dL/dt(max), -39%, H: 69.8 vs. C: 114.6 microm/s), relaxation (dR/dt(max), -37%, 58.2 vs. 92.9 microm/s), [Ca(2+)](iT) (-34%, 0.23 vs. 0.35), and I(Ca,L) (-25%, 4.8 vs. 6.4pA/pF) were all significantly reduced. Compared with controls, in moderate and heavy drinkers, beta(1)-AR protein levels decreased by 23% and 42%, but beta(3)-AR protein increased by 46% and 85%, respectively. These changes were associated with altered myocyte functional responses to beta-AR agonist, isoproterenol (ISO), and beta(3)-AR agonist, BRL-37344 (BRL). Compared with controls, in alcoholic myocytes, ISO (10(-8) M) produced significantly smaller increases in dL/dt(max) (H: 40% vs. C: 71%), dR/dt(max) (37% vs. 52%), [Ca(2+)](iT) (17% vs. 37%), and I(Ca,L) (17% vs. 27%), but BRL (10(-8) M) produced a significantly greater decrease in dL/dt(max) (H: -23% vs. C: -11%), [Ca(2+)](iT) (-30% vs. -11%), and I(Ca,L) (-28% vs. -17%). CONCLUSIONS: Chronic alcohol consumption down-regulates cardiac beta(1)- and up-regulates beta(3)-ARs, contributing to the abnormal response to catecholamines in ACM. The up-regulation of cardiac beta(3)-AR signaling enhances inhibition of LV myocyte contraction and relaxation and exacerbates the dysfunctional [Ca(2+)](i) regulation and, thus, may precede the development of ACM.

Outpatient facility-based order variation in combined imaging.

OBJECTIVE: Combined computed tomography (CT) occurs when one anatomical area is simultaneously imaged both without and with contrast, or two overlapping anatomical areas are imaged concurrently. While this has been studied in a Traditional Medicare population, it has not been studied in other populations subject to prior authorization. This study explores between-facility variation in ordering and receiving orders to render combined CT in a mixed commercial and Medicare Advantage population. METHODS: Orders for CT abdomen (without/with contrast), CT thorax (without/with contrast), and concurrent CT brain and sinus authorized by a prior authorization company from 2013-2017, pertaining to patients with commercial or Medicare Advantage health plans from one national insurer, were extracted. Orders were issued and rendered by both hospitals and nonhospitals. The analysis was performed separately for each anatomical area in two ways: orders were grouped by ordering facility, and by designated rendering facility. For each facility, the ratio of combined to total orders was calculated, and analysis of variance was used to determine whether there were significant differences in this rate by year. The association between health plan type and combined imaging rates was assessed. RESULTS: Combined rates [ratio±standard deviation] for abdomen, thorax, and brain/sinus were 0.306±0.246, 0.089±0.142, and 0.002±0.01 respectively when the analysis was conducted according to ordering facility, and 0.311±0.178, 0.096±0.113, and 0.001±0.006 when the analysis was conducted according to designated rendering facility. Combined CT abdomen and CT thorax rates decreased monotonically from 2013 to 2017, decreases that were significant (P < .01) regardless of whether orders were grouped by ordering or rendering facility. Combined CT abdomen and CT thorax rates significantly differed between orders pertaining to people with commercial and Medicare Advantage plans. DISCUSSION: Variability was greater when orders were grouped by ordering facility, rather than rendering facility. Health plan type may influence whether a patient receives combined CT.

The effects of ethanol consumption on vasculogenesis potential in nonhuman primates.

BACKGROUND: Vasculogenesis is essential to the preservation and repair of damaged or diseased vessels. Alcohol is the most commonly abused drug among young adults, but its effects on vessel growth and repair are unknown. The basis of vascular repair is endothelial progenitor cell (EPC) recruitment to assist in the formation of new vascular network (vasculogenesis). Therefore, the objective of this study was to measure the effects of ethanol consumption on the production, mobilization and vasculogenesis potential EPCs in nonhuman primates. METHODS: Four to five year-old (young adult) male rhesus monkeys consumed monkey chow and water (Control, n = 7), or chow and water + ethanol (Alcohol, 2.45 g/d, n = 7) for 12 months. Peripheral blood (PB) and bone marrow (BM) samples were collected for fluorescence-activated cell-sorting analysis of cell surface antigens (CD45, CD31, CD44, CD133, VEGF-R2 - or KDR); and for capillary formation on Matrigel-coated plates. RESULTS: There were greater numbers of nonhematopoeitic stromal cells (CD45-) and putative mesenchymal progenitor cells (CD45-/CD44+) in the PB and BM of Alcohol versus Control monkeys (p < 0.05). Additionally, there were greater numbers of EPCs (CD45-/CD133+/KDR+) in the BM and PB of Alcohol versus Control monkeys (p < 0.05). However, the EPCs of Alcohol monkeys were less likely to form capillaries on matrigel-coated plates than Control monkeys (p < 0.05). CONCLUSIONS: Ethanol consumption in monkeys markedly increased the production and mobilization of EPCs, but decreased their ability to form capillaries. The pathophysiologic consequences of such effects are unclear, but may represent an ethanol-induced chronic stress on the BM, resulting in EPC.

Behavioral depression and positron emission tomography-determined serotonin 1A receptor binding potential in cynomolgus monkeys.

CONTEXT: Current animal models of depression are inadequate to further our understanding of depression. New models that allow for analysis of cognitive function and sex differences are needed. OBJECTIVE: To characterize serotonin 1A (5-HT(1A)) receptor binding potential (BP) and its relationship with specific characteristics of behavioral depression in cynomolgus monkeys. DESIGN: A 23-month case-control study. SETTING: Small social groups in the laboratory. Subjects Seventeen adult female cynomolgus monkeys. MAIN OUTCOME MEASURES: Serotonin 1A receptor BP was examined by positron emission tomography using the radioligand 4,2"-(methoxyphenyl)-1-[2"-(N-2"-pyridinyl)-p-fluorobenzamido]ethylpiperazine in the raphe, amygdala, hippocampus, and anterior cingulate cortex in monkeys characterized by behavioral observation as depressed or not depressed. Aggression, submission, affiliation, pathologic behaviors, and activity levels were determined by behavioral observation. Heart rate and hypothalamic-pituitary-adrenal function were also determined. RESULTS: Throughout the brain areas examined, there was a reduction in 5-HT(1A) BP in depressed monkeys. The 5-HT(1A) BP in the amygdala and hippocampus was associated with aggression and submission. Friendly interaction, grooming, and locomotion were associated with 5-HT(1A) BP in the left cingulate cortex, whereas attention directed toward the environment was associated with 5-HT(1A) BP in the right cingulate cortex. The 5-HT(1A) receptor BP was inversely associated with heart rate in the raphe, left cingulate, and right amygdala. CONCLUSIONS: This is the fourth in a series of studies that suggest that depressive behavior in adult female cynomolgus monkeys is similar to that observed in humans. It has been observed in 2 large groups of monkeys randomly selected from feral populations, suggesting that the capacity for depression is inherent in the species. This animal model holds promise to further our understanding of the basic mechanisms of affective behavior, the neuropathophysiologic characteristics of depression and the cognitive dysfunction that accompanies them, genetic and environmental factors that may affect depression risk, and the role of reproductive function in the excess depression risk in women.

Changes in nonhuman primate brain function following chronic alcohol consumption in previously naïve animals.

INTRODUCTION: Chronic alcohol abuse is associated with neurophysiological changes in brain activity; however, these changes are not well localized in humans. Non-human primate models of alcohol abuse enable control over many potential confounding variables associated with human studies. The present study utilized high-resolution magnetoencephalography (MEG) to quantify the effects of chronic EtOH self-administration on resting state (RS) brain function in vervet monkeys. METHODS: Adolescent male vervet monkeys were trained to self-administer ethanol (n=7) or an isocaloric malto-dextrin solution (n=3). Following training, animals received 12 months of free access to ethanol. Animals then underwent RS magnetoencephalography (MEG) and subsequent power spectral analysis of brain activity at 32 bilateral regions of interest associated with the chronic effects of alcohol use. RESULTS: demonstrate localized changes in brain activity in chronic heavy drinkers, including reduced power in the anterior cingulate cortex, hippocampus, and amygdala as well as increased power in the right medial orbital and parietal areas. DISCUSSION: The current study is the first demonstration of whole-head MEG acquisition in vervet monkeys. Changes in brain activity were consistent with human electroencephalographic studies; however, MEG was able to extend these findings by localizing the observed changes in power to specific brain regions. These regions are consistent with those previously found to exhibit volume loss following chronic heavy alcohol use. The ability to use MEG to evaluate changes in brain activity following chronic ethanol exposure provides a potentially powerful tool to better understand both the acute and chronic effects of alcohol on brain function.

Chronic ethanol drinking reduces native T-type calcium current in the thalamus of nonhuman primates.

BACKGROUND: Chronic ethanol use is known to disrupt normal sleep rhythms, but the cellular basis for this disruption is unknown. An important contributor to normal sleep patterns is a low-threshold calcium current mediated by T-type calcium channels. The T-type calcium current underlies burst responses in thalamic nuclei that are important to spindle propagation, and we recently observed that this current is sensitive to acute low doses of ethanol. METHODS: We used a combination of current clamp and voltage clamp recordings in an in vitro brain slice preparation of the dorsal lateral geniculate nucleus (LGN) of macaque monkeys that have chronically self-administered ethanol to determine whether chronic ethanol exposure may affect T-type currents. RESULTS: Current clamp recordings from the LGN of ethanol naive macaques showed characteristic burst responses. However, recordings from the LGN in macaques that self-administered ethanol revealed a significant attenuation of bursts across a range of voltages (n=5). Voltage clamp recordings from control LGN neurons (n=16) and neurons (n=29) from brain slices from chronically drinking macaques showed no significant differences (P>0.05) in T-type current kinetics or in the membrane resistance of the thalamic cells between the two cohorts. However, mean T-type current amplitude measured in the chronically drinking animals was reduced by 31% (P<0.01). CONCLUSIONS: We conclude that chronic ethanol self-administration reduces calcium currents in thalamic relay cells without altering underlying current kinetics, which may provide a mechanistic framework for the well-documented disruptions in sleep/wake behavior in subjects with chronic ethanol exposure.

Multi-Atlas Library for Eliminating Normalization Failures in Non-Human Primates.

Current tools for automated skull stripping, normalization, and segmentation of non-human primate (NHP) brain MRI studies typically demonstrate high failure rates. Many of these failures are due to a poor initial estimate for the affine component of the transformation. The purpose of this study is to introduce a multi-atlas approach to overcome these limitations and drive the failure rate to near zero. A library of study-specific templates (SST) spanning three Old World primate species (Macaca fascicularis, M. mulatta, Chlorocebus aethiops) was created using a previously described unbiased automated approach. Several modifications were introduced to the methodology to improve initial affine estimation at the study-specific template level, and at the individual subject level. These involve performing multiple separate normalizations to a multi-atlas library of templates and selecting the best performing template on the basis of a covariance similarity metric. This template was then used as an initialization for the affine component of subsequent skull stripping and normalization procedures. Normalization failure rate for SST generation and individual-subject segmentation on a set of 150 NHP was evaluated on the basis of visual inspection. The previous automated template creation procedure results in excellent skull stripping, segmentation, and atlas labeling across species. Failure rate at the individual-subject level was approximately 1%, however at the SST generation level it was 17%. Using the new multi-atlas approach, failure rate was further reduced to zero for both SST generation and individual subject processing. We describe a multi-atlas library registration approach for driving normalization failures in NHP to zero. It is straightforward to implement, and can have application to a wide variety of existing tools, as well as in difficult populations including neonates and the elderly. This approach is also an important step towards developing fully automated high-throughput processing pipelines that are critical for future high volume multi-center NHP imaging studies for studies of drug abuse and brain health.

Metabolic mapping of the effects of cocaine during the initial phases of self-administration in the nonhuman primate.

Because most human studies of the neurobiological substrates of the effects of cocaine have been performed with drug-dependent subjects, little information is available about the effects of cocaine in the initial phases of drug use before neuroadaptations to chronic exposure have developed. The purpose of the present study, therefore, was to define the substrates that mediate the initial effects of cocaine in a nonhuman primate model of cocaine self-administration using the 2-[14C]deoxyglucose method. Rhesus monkeys were trained to self-administer 0.03 mg/kg per injection (N = 4) or 0.3 mg/kg per injection (N = 4) cocaine and compared with monkeys trained to respond under an identical schedule of food reinforcement (N = 4). Monkeys received 30 reinforcers per session, and metabolic mapping was conducted at the end of the fifth self-administration session. Cocaine self-administration reduced glucose utilization in the mesolimbic system, including the ventral tegmental area, ventral striatum, and medial prefrontal cortex. In addition, metabolic activity was increased in the dorsolateral and dorsomedial prefrontal cortex, as well as in the mediodorsal nucleus of the thalamus. These latter effects are distinctly different from those seen after the noncontingent administration of cocaine, suggesting that self-administration engages circuits beyond those engaged merely by the pharmacological actions of cocaine. The involvement of cortical areas subserving working memory suggests that strong associations between cocaine and the internal and external environment are formed from the very outset of cocaine self-administration. The assessment of the effects of cocaine at a time not readily evaluated in humans provides a baseline from which the effects of chronic cocaine exposure can be investigated.

Incidence of vertebral artery thrombosis in cervical spine trauma: correlation with severity of spinal cord injury.

BACKGROUND AND PURPOSE: The incidence of blunt traumatic vertebral artery dissection/thrombosis varies widely in published trauma series and is associated with spinal trauma. The purpose of this study was to determine the frequency of traumatic vertebral artery thrombosis (VAT) in cervically injured patients by using routine MR angiography (MRA) and MR imaging and identify associations with the severity of neurologic injury. METHODS: A retrospective review of 1283 patients with nonpenetrating cervical spine fractures with or without an associated spinal cord injury (SCI) was performed. Imaging consisted of routine cervical MR imaging and 2D time-of-flight MRA of the neck. The cervical injury level, neurologic level of injury, and American Spinal Injury Association (ASIA) grade were recorded. RESULTS: In this study, 632 patients met the inclusion criteria, 83 (13%) of whom had VAT on the admission MR imaging/MRA. Fifty-nine percent (49/83) of VAT patients had an associated SCI. VAT was significantly more common in motor-complete patients (ASIA A and B, 20%) than in neurologically intact (ASIA E, 11%) cervical spine-injured patients (P = .019). VAT incidence was not significantly different between motor-incomplete (ASIA C and D, 10%) and neurologically intact (ASIA E, 11%) cervical spine-injured patients (P = .840). CONCLUSION: The absence of neurologic symptoms in a patient with cervical spine fracture does not preclude VAT. VAT associated with cervical spinal injury occurs with similar frequency in both neurologically intact (ASIA E) and motor-incomplete patients (ASIA C and D) but is significantly more common in motor-complete SCI (ASIA A and B).

Social stress-associated depression in adult female cynomolgus monkeys (Macaca fascicularis).

This paper describes a behavior pattern in adult female cynomolgus monkeys that has several behavioral and physiological characteristics in common with human depression including reduced body fat, low levels of activity, high heart rate, hypothalamic-pituitary-adrenal (HPA) axis disturbances, and increased mortality. Under certain circumstances, this depressive behavior appears more common in socially stressed subordinate, than dominant, females. This is the first animal model of social stress-related depression in females and the first primate model of adult depression. It is important to have a female animal model of depression because women are more likely to experience a clinically significant depression than men, and depression in women is often associated with changes in reproductive system function. This model is particularly useful because these monkeys have menstrual cycles that are similar to those of women, and those that exhibit depressive behavior have relatively low levels of ovarian steroids. These monkeys may be a useful model of reproductive system-associated mood disorders in females.

Comparison of hippocampal, amygdala, and perirhinal projections to the nucleus accumbens: combined anterograde and retrograde tracing study in the Macaque brain.

A combination of anterograde and retrograde tracing techniques was used to study the projections to the nucleus accumbens from the amygdala, the hippocampal formation (including the entorhinal cortex), and the perirhinal cortex in two species of macaque monkey. To help identify possible subregions within the nucleus accumbens, the distribution of calbindin was examined in two additional monkeys. Although this revealed evidence of "core"- and "shell"-like regions within the accumbens, these different regions could not consistently be related to cytoarchitectonic features. The rostral amygdala sent nearly equivalent projections to both the medial and the lateral portions of nucleus accumbens, whereas projections arising from the middle and caudal amygdala terminated preferentially in the medial division of nucleus accumbens. The basal nucleus was the major source of these amygdala efferents, and there was a crude topography as parts of the basal and accessory basal nuclei terminated in different parts of nucleus accumbens. The subiculum was the major source of hippocampal projections to the nucleus accumbens, but some hippocampal efferents also originated in the parasubiculum, the prosubiculum, the adjacent portion of CA1, and the uncal portion of CA3. These hippocampal projections, which coursed through the fornix, showed a rostrocaudal gradient as more arose in the rostral hippocampus. Hippocampal efferents terminated most densely in the medial and ventral portions of nucleus accumbens, along with light label in the adjacent olfactory tubercle. The entorhinal projections were more evenly distributed between the medial nucleus accumbens and the olfactory tubercle, whereas the perirhinal projections were primarily to the olfactory tubercle. These cortical inputs were less reliant on the fornix. Amygdala and subicular (hippocampal) projections overlapped most completely in the medial division of nucleus accumbens.