Lifelike PixelPrint phantoms for assessing clinical image quality and dose reduction capabilities of a deep learning CT reconstruction algorithm.

Deep learning CT reconstruction (DLR) has become increasingly popular as a method for improving image quality and reducing radiation exposure. Due to their nonlinear nature, these algorithms result in resolution and noise performance which are object-dependent. Therefore, traditional CT phantoms, which lack realistic tissue morphology, have become inadequate for assessing clinical imaging performance. We propose to utilize 3D-printed PixelPrint phantoms, which exhibit lifelike attenuation profiles, textures, and structures, as a better tool for evaluating DLR performance. In this study, we evaluate a DLR algorithm (Precise Image (PI), Philips Healthcare) using a custom PixelPrint lung phantom and perform head-to-head comparisons between DLR, iterative reconstruction, and filtered back projection (FBP) with scans acquired at a broad range of radiation exposures (CTDIvol: 0.5, 1, 2, 4, 6, 9, 12, 15, 19, and 20 mGy). We compared the performance of each resultant image using noise, peak signal to noise ratio (PSNR), structural similarity index (SSIM), feature-based similarity index (FSIM), information theoretic-based statistic similarity measure (ISSM) and universal image quality index (UIQ). Iterative reconstruction at 9 mGy matches the image quality of FBP at 12 mGy (diagnostic reference level) for all metrics, demonstrating a dose reduction capability of 25%. Meanwhile, DLR matches the image quality of diagnostic reference level FBP images at doses between 4 - 9 mGy, demonstrating dose reduction capabilities between 25% and 67%. This study shows that DLR allows for reduced radiation dose compared to both FBP and iterative reconstruction without compromising image quality. Furthermore, PixelPrint phantoms offer more realistic testing conditions compared to traditional phantoms in the evaluation of novel CT technologies. This, in turn, promotes the translation of new technologies, such as DLR, into clinical practice.

Hybrid spectral CT system with clinical rapid kVp-switching x-ray tube and dual-layer detector for improved iodine quantification.

Spectral computed tomography (CT) is a powerful diagnostic tool offering quantitative material decomposition results that enhance clinical imaging by providing physiologic and functional insights. Iodine, a widely used contrast agent, improves visualization in various clinical contexts. However, accurately detecting low-concentration iodine presents challenges in spectral CT systems, particularly crucial for conditions like pancreatic cancer assessment. In this study, we present preliminary results from our hybrid spectral CT instrumentation which includes clinical-grade hardware (rapid kVp-switching x-ray tube, dual-layer detector). This combination expands spectral datasets from two to four channels, wherein we hypothesize improved quantification accuracy for low-dose and low-iodine concentration cases. We modulate the system duty cycle to evaluate its impact on quantification noise and bias. We evaluate iodine quantification performance by comparing two hybrid weighting strategies alongside rapid kVp-switching. This evaluation is performed with a polyamide phantom containing seven iodine inserts ranging from 0.5 to 20 mg/mL. In comparison to alternative methodologies, the maximum separation configuration, incorporating data from both the 80 kVp, low photon energy detector layer and the 140 kVp, high photon energy detector layer produces spectral images containing low quantitative noise and bias. This study presents initial evaluations on a hybrid spectral CT system, leveraging clinical hardware to demonstrate the potential for enhanced precision and sensitivity in spectral imaging. This research holds promise for advancing spectral CT imaging performance across diverse clinical scenarios.

Impact of scatter radiation on spectral quantification performance of first- and second-generation dual-layer spectral computed tomography.

OBJECTIVE: To assess the impact of scatter radiation on quantitative performance of first and second-generation dual-layer spectral computed tomography (DLCT) systems. METHOD: A phantom with two iodine inserts (1 and 2 mg/mL) configured to intentionally introduce high scattering conditions was scanned with a first- and second-generation DLCT. Collimation widths (maximum of 4 cm for first generation and 8 cm for second generation) and radiation dose levels were varied. To evaluate the performance of both systems, the mean CT numbers of virtual monoenergetic images (MonoEs) at different energies were calculated and compared to expected values. MonoEs at 50  versus 150 keV were plotted to assess material characterization of both DLCTs. Additionally, iodine concentrations were determined, plotted, and compared against expected values. For each experimental scenario, absolute errors were reported. RESULTS: An experimental setup, including a phantom design, was successfully implemented to simulate high scatter radiation imaging conditions. Both CT scanners illustrated high spectral accuracy for small collimation widths (1 and 2 cm). With increased collimation (4 cm), the second-generation DLCT outperformed the earlier DLCT system. Further, the spectral performance of the second-generation DLCT at an 8 cm collimation width was comparable to a 4 cm collimation on the first-generation DLCT. A comparison of the absolute errors between both systems at lower energy MonoEs illustrates that, for the same acquisition parameters, the second-generation DLCT generated results with decreased errors. Similarly, the maximum error in iodine quantification was less with second-generation DLCT (0.45  and 0.33 mg/mL for the first and second-generation DLCT, respectively). CONCLUSION: The implementation of a two-dimensional anti-scatter grid in the second-generation DLCT improves the spectral quantification performance. In the clinical routine, this improvement may enable additional clinical benefits, for example, in lung imaging.

Patient-derived PixelPrint phantoms for evaluating clinical imaging performance of a deep learning CT reconstruction algorithm.

Objective. Deep learning reconstruction (DLR) algorithms exhibit object-dependent resolution and noise performance. Thus, traditional geometric CT phantoms cannot fully capture the clinical imaging performance of DLR. This study uses a patient-derived 3D-printed PixelPrint lung phantom to evaluate a commercial DLR algorithm across a wide range of radiation dose levels.Method. The lung phantom used in this study is based on a patient chest CT scan containing ground glass opacities and was fabricated using PixelPrint 3D-printing technology. The phantom was placed inside two different size extension rings to mimic a small- and medium-sized patient and was scanned on a conventional CT scanner at exposures between 0.5 and 20 mGy. Each scan was reconstructed using filtered back projection (FBP), iterative reconstruction, and DLR at five levels of denoising. Image noise, contrast to noise ratio (CNR), root mean squared error, structural similarity index (SSIM), and multi-scale SSIM (MS SSIM) were calculated for each image.Results.DLR demonstrated superior performance compared to FBP and iterative reconstruction for all measured metrics in both phantom sizes, with better performance for more aggressive denoising levels. DLR was estimated to reduce dose by 25%-83% in the small phantom and by 50%-83% in the medium phantom without decreasing image quality for any of the metrics measured in this study. These dose reduction estimates are more conservative compared to the estimates obtained when only considering noise and CNR.Conclusion. DLR has the capability of producing diagnostic image quality at up to 83% lower radiation dose, which can improve the clinical utility and viability of lower dose CT scans. Furthermore, the PixelPrint phantom used in this study offers an improved testing environment with more realistic tissue structures compared to traditional CT phantoms, allowing for structure-based image quality evaluation beyond noise and contrast-based assessments.

Age-related decline in social interaction is associated with decreased c-Fos induction in select brain regions independent of oxytocin receptor expression profiles.

Social behavior decreases with aging, and we have previously found a substantial decline in social investigative behavior of old female rats. In this study we examined the neural activation pattern (c-Fos mRNA) of young (3 month) and old (18 month) female rats after brief 10 min exposure to a novel female rat in order to identify forebrain regions that show selective age-related alterations in their neural response to social investigation. We also measured relative oxytocin receptor expression (Oxtr mRNA) as a possible factor in age-related declines in c-Fos induction after social interaction. Young rats exposed to a social partner had a greater c-Fos mRNA response than those exposed to novel context alone in the lateral septum and septohypothalamic area, with blunted increases evident in old rats. In addition, c-Fos mRNA levels in the lateral septum were positively correlated with social investigative behavior. Interestingly, age-related differences in c-Fos gene induction were unrelated to the local amount of Oxtr expression within specific brain regions, although we found an age-related decline in Oxtr expression in the ventromedial hypothalamus. This functional neuroanatomical characterization may point to certain brain regions that are especially sensitive to age-related declines associated with social interaction behavior.

Prenatal alcohol exposure alters expression of genes involved in cell adhesion, immune response, and toxin metabolism in adolescent rat hippocampus.

Prenatal alcohol exposure (PAE) can result in mild to severe consequences for children throughout their lives, with this range of symptoms referred to as Fetal Alcohol Spectrum Disorders (FASD). These consequences are thought to be linked to changes in gene expression and transcriptional programming in the brain, but the identity of those changes, and how they persist into adolescence are unclear. In this study, we isolated RNA from the hippocampus of adolescent rats exposed to ethanol during prenatal development and compared gene expression to controls. Briefly, dams were either given free access to standard chow ad libitum (AD), pair-fed a liquid diet (PF) or were given a liquid diet with ethanol (6.7% ethanol, ET) throughout gestation (gestational day (GD) 0-20). All dams were given control diet ad libitum beginning on GD 20 and throughout parturition and lactation. Hippocampal tissue was collected from adolescent male and female offspring (postnatal day (PD) 35-36). Exposure to ethanol caused widespread downregulation of many genes as compared to control rats. Gene ontology analysis demonstrated that affected pathways included cell adhesion, toxin metabolism, and immune responses. Interestingly, these differences were not strongly affected by sex. Furthermore, these changes were consistent when comparing ethanol-exposed rats to pair-fed controls provided with a liquid diet and those fed ad libitum on a standard chow diet. We conclude from this study that changes in genetic architecture and the resulting neuronal connectivity after prenatal exposure to alcohol continue through adolescent development. Further research into the consequences of specific gene expression changes on neural and behavioral changes will be vital to our understanding of the FASD spectrum of diseases.

Reproducible spectral CT thermometry with liver-mimicking phantoms for image-guided thermal ablation.

Objectives. Evaluate the reproducibility, temperature tolerance, and radiation dose requirements of spectral CT thermometry in tissue-mimicking phantoms to establish its utility for non-invasive temperature monitoring of thermal ablations.Methods. Three liver mimicking phantoms embedded with temperature sensors were individually scanned with a dual-layer spectral CT at different radiation dose levels during heating (35 °C-80 °C). Physical density maps were reconstructed from spectral results using varying reconstruction parameters. Thermal volumetric expansion was then measured at each temperature sensor every 5 °C in order to establish a correlation between physical density and temperature. Linear regressions were applied based on thermal volumetric expansion for each phantom, and coefficient of variation for fit parameters was calculated to characterize reproducibility of spectral CT thermometry. Additionally, temperature tolerance was determined to evaluate effects of acquisition and reconstruction parameters. The resulting minimum radiation dose to meet the clinical temperature accuracy requirement was determined for each slice thickness with and without additional denoising.Results. Thermal volumetric expansion was robustly replicated in all three phantoms, with a correlation coefficient variation of only 0.43%. Similarly, the coefficient of variation for the slope and intercept were 9.6% and 0.08%, respectively, indicating reproducibility of the spectral CT thermometry. Temperature tolerance ranged from 2 °C to 23 °C, decreasing with increased radiation dose, slice thickness, and iterative reconstruction level. To meet the clinical requirement for temperature tolerance, the minimum required radiation dose ranged from 20, 30, and 57 mGy for slice thickness of 2, 3, and 5 mm, respectively, but was reduced to 2 mGy with additional denoising.Conclusions. Spectral CT thermometry demonstrated reproducibility across three liver-mimicking phantoms and illustrated the clinical requirement for temperature tolerance can be met for different slice thicknesses. The reproducibility and temperature accuracy of spectral CT thermometry enable its clinical application for non-invasive temperature monitoring of thermal ablation.

Patient-derived PixelPrint phantoms for evaluating clinical imaging performance of a deep learning CT reconstruction algorithm.

Objective: Deep learning reconstruction (DLR) algorithms exhibit object-dependent resolution and noise performance. Thus, traditional geometric CT phantoms cannot fully capture the clinical imaging performance of DLR. This study uses a patient-derived 3D-printed PixelPrint lung phantom to evaluate a commercial DLR algorithm across a wide range of radiation dose levels. Approach: The lung phantom used in this study is based on a patient chest CT scan containing ground glass opacities and was fabricated using PixelPrint 3D-printing technology. The phantom was placed inside two different sized extension rings to mimic a small and medium sized patient and was scanned on a conventional CT scanner at exposures between 0.5 and 20 mGy. Each scan was reconstructed using filtered back projection (FBP), iterative reconstruction, and DLR at five levels of denoising. Image noise, contrast to noise ratio (CNR), root mean squared error (RMSE), structural similarity index (SSIM), and multi-scale SSIM (MS SSIM) were calculated for each image. Main Results: DLR demonstrated superior performance compared to FBP and iterative reconstruction for all measured metrics in both phantom sizes, with better performance for more aggressive denoising levels. DLR was estimated to reduce dose by 25-83% in the small phantom and by 50-83% in the medium phantom without decreasing image quality for any of the metrics measured in this study. These dose reduction estimates are more conservative compared to the estimates obtained when only considering noise and CNR with a non-anatomical physics phantom. Significance: DLR has the capability of producing diagnostic image quality at up to 83% lower radiation dose which can improve the clinical utility and viability of lower dose CT scans. Furthermore, the PixelPrint phantom used in this study offers an improved testing environment with more realistic tissue structures compared to traditional CT phantoms, allowing for structure-based image quality evaluation beyond noise and contrast-based assessments.

Reproducible spectral CT thermometry with liver-mimicking phantoms for image-guided thermal ablation.

Objectives: Evaluate the reproducibility, temperature sensitivity, and radiation dose requirements of spectral CT thermometry in tissue-mimicking phantoms to establish its utility for non-invasive temperature monitoring of thermal ablations. Materials and Methods: Three liver mimicking phantoms embedded with temperature sensors were individually scanned with a dual-layer spectral CT at different radiation dose levels during heating and cooling (35 to 80 °C). Physical density maps were reconstructed from spectral results using a range of reconstruction parameters. Thermal volumetric expansion was then measured at each temperature sensor every 5°C in order to establish a correlation between physical density and temperature. Linear regressions were applied based on thermal volumetric expansion for each phantom, and coefficient of variation for fit parameters was calculated to characterize reproducibility of spectral CT thermometry. Additionally, temperature sensitivity was determined to evaluate the effect of acquisition parameters, reconstruction parameters, and image denoising. The resulting minimum radiation dose to meet the clinical temperature sensitivity requirement was determined for each slice thickness, both with and without additional denoising. Results: Thermal volumetric expansion was robustly replicated in all three phantoms, with a correlation coefficient variation of only 0.43%. Similarly, the coefficient of variation for the slope and intercept were 9.6% and 0.08%, respectively, indicating reproducibility of the spectral CT thermometry. Temperature sensitivity ranged from 2 to 23 °C, decreasing with increased radiation dose, slice thickness, and iterative reconstruction level. To meet the clinical requirement for temperature sensitivity, the minimum required radiation dose ranged from 20, 30, and 57 mGy for slice thickness of 2, 3, and 5 mm, respectively, but was reduced to 2 mGy with additional denoising. Conclusions: Spectral CT thermometry demonstrated reproducibility across three liver-mimicking phantoms and illustrated the clinical requirement for temperature sensitivity can be met for different slice thicknesses. Moreover, additional denoising enables the use of more clinically relevant radiation doses, facilitating the clinical translation of spectral CT thermometry. The reproducibility and temperature accuracy of spectral CT thermometry enable its clinical application for non-invasive temperature monitoring of thermal ablation.

Assessment of neuroinflammation in the aging hippocampus using large-molecule microdialysis: Sex differences and role of purinergic receptors.

Aging is associated with an enhanced neuroinflammatory response to acute immune challenge, often termed "inflammaging." However, there are conflicting reports about whether baseline levels of inflammatory markers are elevated under ambient conditions in the aging brain, or whether such changes are observed predominantly in response to acute challenge. The present studies utilized two distinct approaches to assess inflammatory markers in young and aging Fischer 344 rats. Experiment 1 examined total tissue content of inflammatory markers from hippocampus of adult (3 month), middle-aged (12 month), and aging (18 month) male Fischer (F) 344 rats using multiplex analysis (23-plex). Though trends emerged for several cytokines, no significant differences in basal tissue content were observed across the 3 ages examined. Experiment 2 measured extracellular concentrations of inflammatory factors in the hippocampus from adult (3 month) and aging (18 month) males and females using large-molecule in vivo microdialysis. Although few significant aging-related changes were observed, robust sex differences were observed in extracellular concentrations of CCL3, CCL20, and IL-1α. Experiment 2 also evaluated the involvement of the P2X7 purinergic receptor in neuroinflammation using reverse dialysis of the selective agonist BzATP. BzATP produced an increase in IL-1α and IL-1ß release and rapidly suppressed the release of CXCL1, CCL2, CCL3, CCL20, and IL-6. Other noteworthy sex by aging trends were observed in CCL3, IL-1ß, and IL-6. Together, these findings provide important new insight into late-aging and sex differences in neuroinflammation, and their regulation by the P2X7 receptor.

Quantitative positron emission tomography imaging in the presence of iodinated contrast media using electron density quantifications from dual-energy computed tomography.

PURPOSE: As preparation for future positron emission tomography (PET)/dual-energy computed tomography (DECT)T imaging modality and new possible clinical applications, the study aimed to evaluate the utility of clinically available spectral results from a DECT system for improving attenuation corrections of PET acquisitions in the presence of iodinated contrast media. The dependence of the accuracy of PET quantification values, reconstructed with conventional and spectral-based attenuation corrections, was examined as a function of the amount of iodine content and x-ray radiation exposure. METHODS: Measurements were performed on commercial PET/CT and DECT systems, using a semi-anthropomorphic phantom with seven centrifuge tubes in its bore. Five different configurations of tube contents were scanned by both PET/CT and DECT. With the aim of mimicking clinically observed concentrations, in all phantom configurations the center tube contained a high concentration of radionuclide while the peripheral tubes contained a lower concentration of radionuclide. Iodine content was incrementally increased between phantom configurations by replacing iodine-free tubes with tubes that contained the original radionuclide concentration within a 10 mg/ml iodine dilution. DECT-based attenuation correction maps were generated by scaling electron density spectral results into corresponding 511 keV photon linear attenuation coefficients. RESULTS: Mean SUV values obtained from the nominal PET reconstruction, using conventional CT images as input for the attenuation correction, demonstrate a monotonic increase of 8.6% when the water and radionuclide mixtures were replaced by iodine, water, and radionuclide (same level of activity) mixture. Mean SUV values obtained from the DECT-based reconstruction, in which the attenuation correction utilizes electron density values as input, demonstrate different, more stable behavior across all iodine insert configurations, with a standard deviation to mean ratio of less than 1%. This observed behavior was independent of the area size used for measurement. A minor radiation dose dependency of the electron density values (below 0.5%) was observed. This resulted in consistent (iodine independent) PET quantification behavior, which persisted even at the lowest radiation dose levels tested in our experiment, that is, 25% of the radiation dose utilized for CT acquisition in the clinical PET/CT protocol. CONCLUSIONS: Utilization of DECT-generated electron density estimations for attenuation correction benefit PET quantification consistency in the presence of iodine and at nominal and low DECT radiation exposure levels. The ability to correctly account for iodinated contrast media in PET acquisitions will allow the development of new clinical applications that rely on the quantitative capabilities of spectral CT technologies and modern PET systems.

Fibrillization of 40-Residue ß-Amyloid Peptides in Membrane-Like Environments Leads to Different Fibril Structures and Reduced Molecular Polymorphisms.

The molecular-level polymorphism in ß-Amyloid (Aß) fibrils have recently been considered as a pathologically relevant factor in Alzheimer's disease (AD). Studies showed that the structural deviations in human-brain-seeded Aß fibrils potentially correlated with the clinical histories of AD patients. For the 40-residue Aß (Aß40) fibrils derived from human brain tissues, a predominant molecular structure was proposed based on solid-state nuclear magnetic resonance (ssNMR) spectroscopy. However, previous studies have shown that the molecular structures of Aß 40 fibrils were sensitive to their growth conditions in aqueous environments. We show in this work that biological membranes and their phospholipid bilayer mimics serve as environmental factors to reduce the structural heterogeneity in Aß40 fibrils. Fibrillization in the presence of membranes leads to fibril structures that are significantly different to the Aß40 fibrils grown in aqueous solutions. Fibrils grown from multiple types of membranes, including the biological membranes extracted from the rats' synaptosomes, shared similar ssNMR spectral features. Our studies emphasize the biological relevance of membranes in Aß40 fibril structures and fibrillization processes.

PennPET Explorer: Design and Preliminary Performance of a Whole-Body Imager.

We report on the development of the PennPET Explorer whole-body imager. Methods: The PennPET Explorer is a multiring system designed with a long axial field of view. The imager is scalable and comprises multiple 22.9-cm-long ring segments, each with 18 detector modules based on a commercial digital silicon photomultiplier. A prototype 3-segment imager has been completed and tested with an active 64-cm axial field of view. Results: The instrument design is described, and its physical performance measurements are presented. These include sensitivity of 55 kcps/MBq, spatial resolution of 4.0 mm, energy resolution of 12%, timing resolution of 256 ps, and a noise-equivalent count rate above 1,000 kcps beyond 30 kBq/mL. After an evaluation of lesion torso phantoms to characterize quantitative accuracy, human studies were performed on healthy volunteers. Conclusion: The physical performance measurements validated the system design and led to high-quality human studies.

From adolescence to late aging: A comprehensive review of social behavior, alcohol, and neuroinflammation across the lifespan.

The passage of time dictates the pace at which humans and other organisms age but falls short of providing a complete portrait of how environmental, lifestyle and underlying biological processes contribute to senescence. Two fundamental features of the human experience that change dramatically across the lifespan include social interactions and, for many, patterns of alcohol consumption. Rodent models show great utility for understanding complex interactions among aging, social behavior and alcohol use and abuse, yet little is known about the neural changes in late aging that contribute to the natural decline in social behavior. Here, we posit that aging-related neuroinflammation contributes to the insipid loss of social motivation across the lifespan, an effect that is exacerbated by patterns of repeated alcohol consumption observed in many individuals. We provide a comprehensive review of (i) neural substrates crucial for the expression of social behavior under non-pathological conditions; (ii) unique developmental/lifespan vulnerabilities that may contribute to the divergent effects of low-and high-dose alcohol exposure; and (iii) aging-associated changes in neuroinflammation that may sit at the intersection between social processes and alcohol exposure. In doing so, we provide an overview of correspondence between lifespan/developmental periods between common rodent models and humans, give careful consideration to model systems used to aptly probe social behavior, identify points of coherence between human and animal models, and point toward a multitude of unresolved issues that should be addressed in future studies. Together, the combination of low-dose and high-dose alcohol effects serve to disrupt the normal development and maintenance of social relationships, which are critical for both healthy aging and quality of life across the lifespan. Thus, a more complete understanding of neural systems-including neuroinflammatory processes-which contribute to alcohol-induced changes in social behavior will provide novel opportunities and targets for promoting healthy aging.

Late aging-associated increases in L-DOPA-induced dyskinesia are accompanied by heightened neuroinflammation in the hemi-parkinsonian rat.

Aging is a primary risk factor for the development of Parkinson's disease (PD), and aging differentially predicts the incidence of L-DOPA-induced dyskinesia (LID). The goal of this work was to establish whether late aging-associated exacerbation of LID would be related to neuroinflammation in the hemi-parkinsonian rat. Two studies were conducted in which adult (3 months) and aged (18 months) male Fischer 344 rats bearing unilateral 6-hydroxydopamine lesions of the medial forebrain bundle were injected acutely with vehicle or L-DOPA (6 mg/kg). LID was quantified, and neuroinflammation was assessed postmortem via gene expression markers in the striatum (experiment 1) or through concurrent large-molecule microdialysis (experiment 2). In addition to exacerbating LID despite similar levels of striatal dopamine loss, late aging was associated with persistently elevated IL-1ß gene expression ipsilateral to lesion, as well as a trend toward greater extracellular concentrations of IL-1ß in response to acute L-DOPA treatment. In contrast, aged sham-operated rats displayed greater extracellular IL-6. Taken together, these data demonstrate an age-related vulnerability to LID and highlight potential neuroinflammatory mediators associated with these effects.

Impact of housing conditions on social behavior, neuroimmune markers, and oxytocin receptor expression in aged male and female Fischer 344 rats.

Aging is associated with a substantial decline in social behavior, whereas positive social interaction can improve overall health in aged individuals. In laboratory rodents, manipulations of the social environment across the lifespan have been shown to affect social behavior. Therefore, we examined the effects of long-term (5-6 weeks) housing conditions (alone, with one adult, or with two adults) on social behavior and the expression of neuroinflammation-related genes as well as oxytocin receptor (OXTR) gene expression in brain areas associated with social behavior regulation in aged male and female Fischer (F) 344 rats. Single-housed males and females exhibited increased social investigation, relative to pair-housed rats (one aged and one adult). Triple-housed (one aged and two adults) aged males exhibited lower levels of social investigation, relative to triple-housed aged females. Aged females were more socially active that their male counterparts. Although social housing condition significantly affected social behavior in males, it had no impact on cytokine gene expression in the paraventricular nucleus of hypothalamus (PVN), bed nucleus of the stria terminalis (BNST) or medial amygdala (MeA). However, in triple-housed aged females, who exhibited social behavior comparable to their single- and pair-housed counterparts, there was a significant increase in the expression of IL-1ß and IL-6 mRNA in the MeA. No changes in cytokine gene expression were observed in the PVN or BNST, indicating that the increased expression of cytokines in the MeA was not a result of a generalized increase in neuroinflammation. Single-housed males and females exhibited elevated OXTR gene expression in the BNST. Taken together, these data indicate that manipulations of the social environment in late aging significantly influenced social interactions with a novel partner and gene expression in social behavior circuits and that these effects are sex-specific.

Late aging alters behavioral sensitivity to ethanol in a sex-specific manner in Fischer 344 rats.

Responsiveness to ethanol (EtOH) differs as a function of age. Adolescent rodents are less sensitive than adults to the sedative effects of EtOH, whereas they show enhanced sensitivity to EtOH-induced social facilitation. Late aging is associated with a natural decline in social behavior and aging-related peculiarities in sensitivity to EtOH have been largely unexplored. Whether there are sex differences in the behavioral response to EtOH during late aging remains unknown. Thus, behavioral responses to EtOH in male and female Fischer (F) 344 rats aged 4-5 months (adult) and 19-20 months (aging) were examined. First, the effects of saline and EtOH (0.5 and 0.75 g/kg) on social interaction were assessed. Social investigation and contact behavior were lower in aging animals and higher in females. Interestingly, in aged females, social contact behavior was increased following a 0.5 g/kg EtOH dose, whereas the same dose suppressed social contact in aged males. Behavioral sensitivity to the sedative effects of 3.0 and 3.5 g/kg EtOH was assessed with the loss of righting reflex (LORR) test. Although latency to LORR did not differ as a function of age or sex, aged rats showed significantly greater LORR duration and significantly lower blood ethanol concentrations (BECs) at regaining of the righting reflex relative to adults. In addition, females had a lower LORR duration, regardless of age; no sex differences were evident in BECs at awakening. In a second experiment, blood ethanol concentrations (BECs) over time were assessed following 0.75, 1.5, and 3.0 g/kg EtOH in 3-, 12-, and 18-month-old male and female F344 rats. Aged rats had higher peak BECs following 3.0 g/kg EtOH, whereas few age or sex differences were apparent at lower doses. Taken together, these data indicate that late aging is associated with altered sensitivity to the social facilitating effects and sedative effects of EtOH.

Stereological Analysis of Microglia in Aged Male and Female Fischer 344 Rats in Socially Relevant Brain Regions.

Aging is associated with a substantial decline in the expression of social behavior as well as increased neuroinflammation. Since immune activation and subsequent increased expression of cytokines can suppress social behavior in young rodents, we examined age and sex differences in microglia within brain regions critical to social behavior regulation (PVN, BNST, and MEA) as well as in the hippocampus. Adult (3-month) and aged (18-month) male and female F344 (N = 26, n = 5-8/group) rats were perfused and Iba-1 immunopositive microglia were assessed using unbiased stereology and optical density. For stereology, microglia were classified based on the following criteria: (1) thin ramified processes, (2) thick long processes, (3) stout processes, or (4) round/ameboid shape. Among the structures examined, the highest density of microglia was evident in the BNST and MEA. Aged rats of both sexes displayed increased total number of microglia number exclusively in the MEA. Sex differences also emerged, whereby aged females (but not males) displayed greater total number of microglia in the BNST relative to their young adult counterparts. When morphological features of microglia were assessed, aged rats exhibited increased soma size in the BNST, MEA, and CA3. Together, these findings provide a comprehensive characterization of microglia number and morphology under ambient conditions in CNS sites critical for the normal expression of social processes. To the extent that microglia morphology is predictive of reactivity and subsequent cytokine release, these data suggest that the expression of social behavior in late aging may be adversely influenced by heightened inflammation.

Optimization-Based Image Reconstruction From Low-Count, List-Mode TOF-PET Data.

OBJECTIVE: We investigate an optimization-based approach to image reconstruction from list-mode data in digital time-of-flight (TOF) positron emission tomography (PET) imaging. METHOD: In the study, the image to be reconstructed is designed as a solution to a convex, non-smooth optimization program, and a primal-dual algorithm is developed for image reconstruction by solving the optimization program. The algorithm is first applied to list-mode TOF-PET data of a typical count level from physical phantoms and a human subject. Subsequently, we explore the algorithm's potential for image reconstruction in low-dose and/or fast TOF-PET imaging of practical interest by applying the algorithm to list-mode TOF-PET data of different, low-count levels from the same physical phantoms and human subject. RESULTS: Visual inspection and quantitative-metric analysis reveal that the optimization reconstruction approach investigated can yield images with enhanced spatial and contrast resolution, suppressed image noise, and increased axial volume coverage over the reference images obtained with a standard clinical reconstruction algorithm especially for low-dose TOF-PET data. SIGNIFICANCE: The optimization-based reconstruction approach can be exploited for yielding insights into potential quality upper bound of reconstructed images in, and design of scanning protocols of, TOF-PET imaging of practical significance.

Analysis of c-Fos induction in response to social interaction in male and female Fisher 344 rats.

Sex differences in the expression of social behavior are typically apparent in adolescent and adult rats. While the neurobiology underlying juvenile social play behavior has been well characterized, less is known about discrete brain regions involved in adult responsiveness to a same sex peer. Furthermore, whether adult males and females differ in their responsiveness to a social interaction in terms of neuronal activation indexed via immediate early gene (IEG) expression remains to be determined. Thus, the present study was designed to identify key sites relevant to the processing of sensory stimuli (generally) or social stimuli (specifically) after brief exposure to a same-sex social partner by assessing IEG expression. Four-month-old male and female Fisher (F) 344 rats (N=38; n=5-8/group) were either left undisturbed in their home cage as controls (HCC), exposed to a testing context alone for 30min (CXT), or were placed in the context for 20min and then allowed to socially interact (SI) with a sex-matched conspecific for 10min. Females demonstrated greater levels of social behavior, relative to males. Analysis of c-Fos induction revealed that females exhibited greater c-Fos expression in the prefrontal cortex, regardless of condition. In many brain regions, induction was similar in the CXT and SI groups. However, in the bed nucleus of the stria terminalis (BNST), females exhibited greater c-Fos induction in response to the social interaction relative to their male counterparts, indicating a sex difference in responsivity to social stimuli. Taken together, these data suggest that the BNST is a sexually dimorphic region in terms of activation in response to social stimuli.