Safety and feasibility of transcranial direct current stimulation stratified by corticospinal organization in children with hemiparesis.

Children with hemiparesis (CWH) due to stroke early in life face lifelong impairments in motor function. Transcranial direct current stimulation (tDCS) may be a safe and feasible adjuvant therapy to augment rehabilitation. Given the variability in outcomes following tDCS, tailored protocols of tDCS are required. We evaluated the safety, feasibility, and preliminary effects of a single session of targeted anodal tDCS based on individual corticospinal tract organization on corticospinal excitability. Fourteen CWH (age = 13.8 ± 3.63) were stratified into two corticospinal organization subgroups based on transcranial magnetic stimulation (TMS)-confirmed motor evoked potentials (MEP): ipsilesional MEP presence (MEPIL+) or absence (MEPIL-). Subgroups were randomized to real anodal or sham tDCS (1.5 mA, 20 min) applied to the ipsilesional (MEPIL + group) or contralesional (MEPIL- group) hemisphere combined with hand training. Safety was assessed with questionnaires and motor function evaluation, and corticospinal excitability was assessed at baseline and every 15 min for 1 h after tDCS. No serious adverse events occurred and anticipated minor side effects were reported and were self-limiting. Six of 14 participants had consistent ipsilesional MEPs (MEPIL + group). Paretic hand MEP amplitude increased in 5/8 participants who received real anodal tDCS to either the ipsilesional or contralesional hemisphere (+80% change). Application of tDCS based on individual corticospinal organization was safe and feasible with expected effects on excitability, indicating the potential for tailored tDCS protocols for CWH. Additional research involving expanded experimental designs is needed to confirm these effects and to determine if this approach can be translated into a clinically relevant intervention.

Anodal Contralesional tDCS Enhances CST Excitability Bilaterally in an Adolescent with Hemiparetic Cerebral Palsy: A Brief Report.

Hemiparetic cerebral palsy (HCP), weakness on one side of the body typically caused by perinatal stroke, is characterized by lifelong motor impairments related to alterations in the corticospinal tract (CST). CST reorganization could be a useful biomarker to guide applications of neuromodulatory interventions, such as transcranial direct current stimulation (tDCS), to improve the effectiveness of rehabilitation therapies. We evaluated an adolescent with HCP and CST reorganization who demonstrated persistent heightened CST excitability in both upper limbs following anodal contralesional tDCS. The results support further investigation of targeted tDCS as an adjuvant therapy to traditional neurorehabilitation for upper limb function.

Disrupted Access to Therapies and Impact on Well-Being During the COVID-19 Pandemic for Children With Motor Impairment and Their Caregivers.

OBJECTIVES: The aim of this study was to determine the impact of the COVID-19 pandemic on access to rehabilitation therapies and the impact of changes in therapy access on the physical and mental well-being of children with motor impairment and their caregivers. DESIGN: Caregivers of children younger than 18 yrs with childhood-onset motor impairment (primarily cerebral palsy) completed an anonymous survey through the online platform REDCap between May 5 and July 13, 2020. RESULTS: The survey was completed by 102 participants. Before the pandemic, 92 of 102 children (90%) were receiving one or more therapies; at the time surveyed, 55 children (54%) were receiving any therapies (P < 0.001). More than 40% of the sample reported increased child stress, decreased physical activity, and/or decline in mobility/movement. Participants who reported a decrease in number of therapies at the time surveyed more frequently reported lower satisfaction with treatment delivery (P < 0.001), a decline in child's mobility (P = 0.001), and increased caregiver stress (P = 0.004). Five qualitative themes were identified from open-ended question responses related to therapies and well-being. CONCLUSIONS: Access to pediatric rehabilitation therapies was disrupted during COVID-19. Disrupted access may be related to impact on physical and mental health. With the expansion of telehealth, caregiver and child feedback should be incorporated to optimize benefit.

Evaluating transcranial magnetic stimulation (TMS) induced electric fields in pediatric stroke.

Transcranial magnetic stimulation (TMS) is an increasingly popular tool for stroke rehabilitation. Consequently, researchers have started to explore the use of TMS in pediatric stroke. However, the application of TMS in a developing brain with pathologies comes with a unique set of challenges. The effect of TMS-induced electric fields has not been explored in children with stroke lesions. Here, we used finite element method (FEM) modeling to study how the electric field strength is affected by the presence of a lesion. We created individual realistic head models from MRIs (n = 6) of children with unilateral cerebral palsy due to perinatal stroke. We conducted TMS electric field simulations for coil locations over lesioned and non-lesioned hemispheres. We found that the presence of a lesion can strongly affect the electric field distribution. On the group level, the mean electric field strength did not differ between lesioned and non-lesioned hemispheres but exhibited a greater variability in the lesioned hemisphere. Other factors such as coil-to-cortex distance have a strong influence on the TMS electric field even in the presence of lesions. Our study has important implications for the delivery of TMS in children with brain lesions with respect to TMS dosing and coil placement.

Motor Evoked Potentials as Potential Biomarkers of Early Atypical Corticospinal Tract Development in Infants with Perinatal Stroke.

Diagnosis of cerebral palsy (CP) after perinatal stroke is often delayed beyond infancy, a period of rapid neuromotor development with heightened potential for rehabilitation. This study sought to assess whether the presence or absence of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) could be an early biomarker of atypical development within the first year of life. In 10 infants with perinatal stroke, motor outcome was assessed with a standardized movement assessment. Single-pulse TMS was utilized to assess presence of MEPs. Younger infants (3-6 months CA, n = 5, 4/5 (80%)) were more likely to present with an MEP from the more-affected hemisphere (MAH) compared to older infants (7-12 months CA, n = 5, 0/5, (0%)) (p = 0.048). Atypical movement was demonstrated in the majority of infants with an absent MEP from the MAH (5/6, 83%) compared to those with a present MEP (1/4, 25%) (p = 0.191). We found that age influences the ability to elicit an MEP from the MAH, and motor outcome may be related to MAH MEP absence. Assessment of MEPs in conjunction with current practice of neuroimaging and motor assessments could promote early detection and intervention in infants at risk of CP.

Neurite orientation dispersion and density imaging quantifies corticospinal tract microstructural organization in children with unilateral cerebral palsy.

Children with unilateral cerebral palsy (UCP) due to early brain injury exhibit disrupted connectivity of corticospinal tracts (CSTs), which can be quantified using diffusion-weighted magnetic resonance imaging (DWI). Diffusion tensor imaging (DTI) is commonly used to quantify white matter organization, however, this model lacks the biological specificity to accurately describe underlying microstructural properties. Newer approaches, such as neurite orientation dispersion and density imaging (NODDI), may provide more biologically accurate information regarding CST microstructure. In this study, we directly compared metrics of CST microstructure using NODDI and DTI models to characterize the microstructural organization of corticospinal pathways. Twenty participants with UCP participating in a neuromodulation/rehabilitation intervention underwent imaging including multi-shell DWI; 10 participants' datasets were adequately completed for neuroimaging analysis. Task fMRI-guided probabilistic tractography from motor cortex to brainstem was performed at baseline and follow-up to reconstruct the CSTs. Diffusion metrics were compared between hemispheres at baseline, and between baseline and follow-up to test for intervention effects. Correlation analyses were used to compare baseline metrics to changes in hand function following the intervention. DTI results showed that mean fractional anisotropy in lesioned and nonlesioned CSTs did not significantly differ, but mean, axial, and radial diffusivity were greater in the lesioned CST. For NODDI, intracellular volume fraction (ICVF) and orientation dispersion index (ODI) were lower in the lesioned CST. Unimanual function was strongly correlated with ICVF, but not FA. NODDI may reveal distinct properties of CST microstructure that are linked to motor function, indicating their potential in characterizing brain structure and development.

Influence of Combined Transcranial Direct Current Stimulation and Motor Training on Corticospinal Excitability in Children With Unilateral Cerebral Palsy.

Combined non-invasive brain stimulation (NIBS) and rehabilitation interventions have the potential to improve function in children with unilateral cerebral palsy (UCP), however their effects on developing brain function are not well understood. In a proof-of-principle study, we used single-pulse transcranial magnetic stimulation (TMS) to measure changes in corticospinal excitability and relationships to motor performance following a randomized controlled trial consisting of 10 days of combined constraint-induced movement therapy (CIMT) and cathodal transcranial direct current stimulation (tDCS) applied to the contralesional motor cortex. Twenty children and young adults (mean age = 12 years, 9 months, range = 7 years, 7 months, 21 years, 7 months) with UCP participated. TMS testing was performed before, after, and 6 months after the intervention to measure motor evoked potential (MEP) amplitude and cortical silent period (CSP) duration. The association between neurophysiologic and motor outcomes and differences in excitability between hemispheres were examined. Contralesional MEP amplitude decreased as hypothesized in five of five participants receiving active tDCS immediately after and 6 months after the intervention, however no statistically significant differences between intervention groups were noted for MEP amplitude [mean difference = -323.9 µV, 95% CI = (-989, 341), p = 0.34] or CSP duration [mean difference = 3.9 ms, 95% CI = (-7.7, 15.5), p = 0.51]. Changes in corticospinal excitability were not statistically associated with improvements in hand function after the intervention. Across all participants, MEP amplitudes measured in the more-affected hand from both contralesional (mean difference = -474.5 µV) and ipsilesional hemispheres (-624.5 µV) were smaller compared to the less-affected hand. Assessing neurophysiologic changes after tDCS in children with UCP provides an understanding of long-term effects on brain excitability to help determine its potential as a therapeutic intervention. Additional investigation into the neurophysiologic effects of tDCS in larger samples of children with UCP are needed to confirm these findings.

Bimanual Skill Learning after Transcranial Direct Current Stimulation in Children with Unilateral Cerebral Palsy: A Brief Report.

Bimanual skills are important for goal-oriented activities. Children with unilateral cerebral palsy (UCP) have deficits in unimanual and bimanual motor control and learning. The application of non-invasive brain stimulation with existing motor training may further promote motor learning; however, the effects of stimulation on bimanual learning have not been examined. Here, we assessed the performance of a novel bimanual skill (modified Speed Stacks task) in eight children with UCP before, during, and after a combined motor training and brain stimulation intervention. Participants received 10 days (120 min/day) of goal-oriented bimanual therapy combined initially with transcranial direct current stimulation (tDCS, 20 min/day). Results showed task improvement tapered (p < 0.001) during and after the intervention and task variability decreased in 6/8 participants, indicating the potential impact of novel rehabilitation to improve skill learning in children with UCP. Future work is required to understand how both tDCS and bimanual training contribute to learning bimanual tasks.

Safety and Feasibility of Transcranial Magnetic Stimulation as an Exploratory Assessment of Corticospinal Connectivity in Infants After Perinatal Brain Injury: An Observational Study.

BACKGROUND: Perinatal brain injuries often impact the corticospinal system, leading to motor impairment and cerebral palsy. Although transcranial magnetic stimulation (TMS) has been widely used to study corticospinal connectivity in adults and older children, similar studies of young infants are limited. OBJECTIVES: The objective was to establish the safety and feasibility of advanced TMS assessments of the corticospinal connectivity of young infants with perinatal brain injury. DESIGN: This was a pilot, cross-sectional study of 3- to 12-month-old (corrected age) infants with perinatal stroke or intracranial hemorrhage. METHODS: Six participants (2 term, 4 preterm) were assessed with stereotactic neuronavigation-guided TMS. Single-pulse TMS was applied to each hemisphere and responses were recorded simultaneously from both upper limbs. During data collection, vital signs and stress responses were measured to assess safety. Developmental motor outcomes were evaluated using the General Movements Assessment and Bayley Scales of Infant and Toddler Development (3rd edition). A clinical diagnosis of cerebral palsy was recorded, if available. RESULTS: No adverse events occurred during TMS testing. All sessions were well tolerated. Contralateral motor evoked responses were detected in 4 of 6 participants. Both contralateral and ipsilateral responses were observed in 2 of 6 participants. LIMITATIONS: TMS responses were not obtained in all participants. This could be related to the location of brain injury or developmental stage of the corticospinal system controlling the wrist flexor muscle group from which responses were recorded. CONCLUSIONS: This study provides a summary of the framework for performing novel TMS assessments in infants with perinatal brain injury. Implementing this approach to measure corticospinal connectivity in hypothesis-driven studies in young infants appears to be justified. Such studies could inform the characterization of corticospinal development and the neural mechanisms driving recovery following early interventions.

A Case of Apparent Upper-Body Freezing in Parkinsonism while Using a Wheelchair.

Freezing of gait (FOG) is a common, disabling gait disturbance in Parkinson's disease (PD) and other Parkinsonian syndromes. Freezing also occurs during non-gait movements involving the upper limbs. The mechanisms underlying freezing are complex, likely involving motor, cognitive, and sensory systems that contribute to the episodes. Here, we reported a 60-year-old female with a 24-year history of parkinsonism who experienced significant FOG when ambulatory. Disease progression resulted in her permanent use of a powered wheelchair. While using the power chair, the patient experiences apparent paroxysmal freezing in the hand and arm used to steer and propel the chair. These episodes, some lasting up to several minutes, occur only in circumstances (e.g., entering and leaving an elevator) that are similar to environments known to elicit and exacerbate FOG. Episodes are transient and can be volitionally interrupted by the patient but sometimes require external assistance. Therapeutic intervention for this type of potential freezing has yet to be determined. This case may provide insight into the complex nature of freezing behavior and suggests a need for new approaches to treating non-traditional freezing behavior.

Freezing of gait is associated with increased saccade latency and variability in Parkinson's disease.

OBJECTIVE: Freezing of gait (FOG) is a locomotor disturbance in Parkinson disease (PD) related to impaired motor automaticity. In this study, we investigated the impact of freezing on automaticity in the oculomotor system using an anti-saccade paradigm. METHODS: Subjects with PD with (PD-FOG, n=13) and without (PD-NON, n=13) FOG, and healthy age-matched controls (CTRL, n=12) completed automatic pro-saccades and non-automatic anti-saccades. Primary outcomes were saccade latency, velocity, and gain. RESULTS: PD-FOG (pro-saccade latency=271ms, anti-saccade latency=412ms) were slower to execute both types of saccades compared to PD-NON (253ms, 330ms) and CTRL (246ms, 327ms). Saccade velocity and gain variability was also increased in PD-FOG. CONCLUSIONS: Saccade performance was affected in PD-FOG for both types of saccades, indicating differences in automaticity and control in the oculomotor system related to freezing. SIGNIFICANCE: These results and others show that FOG impacts non-gait motor functions, suggesting global motor impairment in PD-FOG.

Reduced after-effects following podokinetic adaptation in people with Parkinson's disease and freezing of gait.

INTRODUCTION: Gait dysfunction is common in people with Parkinson's disease (PD). Freezing of gait (FOG) is one such gait disturbance that significantly impacts mobility and quality of life in PD. Recent evidence suggests that cerebellar connectivity may differ in people with PD and FOG (PD+FOG) relative to those without FOG (PD-FOG). Investigation of gait adaptation, or the ability to change gait patterns in response to external perturbations, is cerebellum-dependent, is a practical means of probing cerebellar integrity and may provide additional insights regarding the FOG phenomenon. METHODS: In this study, we investigated gait adaptation in PD and FOG by measuring after-effects, namely whole-body rotation, following stepping on a rotating disc in PD+FOG compared to PD-FOG and older healthy adults. We refer to the period of stepping on the rotating disc as the podokinetic (PK) stimulation and after-effects as podokinetic after-rotation (PKAR). Our primary measure of adaptation was the magnitude and rate of decay of the after-effects. RESULTS: We noted that PKAR was diminished in PD+FOG compared to the other groups, indicating reduced storage of the adapted gait pattern in PD+FOG. In the PD groups, FOG explained about 20% of the variability in peak velocity. Furthermore, these differences were independent of stepping cadence or motor sign severity. CONCLUSION: Our results show that gait adaptation is impaired in PD+FOG, suggesting the cerebellum may be differentially impacted in PD+FOG compared to PD-FOG. This supports previous neuroimaging evidence of cerebellar dysfunction in PD+FOG. Overall, these data further our understanding of gait deficits in PD+FOG.

How do age and nature of the motor task influence visuomotor adaptation?

Visuomotor adaptation with prism glasses is a paradigm often used to understand how the motor system responds to visual perturbations. Both reaching and walking adaptation have been documented, but not directly compared. Because the sensorimotor environment and demands are different between reaching and walking, we hypothesized that characteristics of prism adaptation, namely rates and aftereffects, would be different during walking compared to reaching. Furthermore, we aimed to determine the impact of age on motor adaptation. We studied healthy younger and older adults who performed visually guided reaching and walking tasks with and without prism glasses. We noted age effects on visuomotor adaptation, such that older adults adapted and re-adapted slower compared to younger adults, in accord with previous studies of adaptation in older adults. Interestingly, we also noted that both groups adapted slower and showed smaller aftereffects during walking prism adaptation compared to reaching. We propose that walking adaptation is slower because of the complex multi-effector and multi-sensory demands associated with walking. Altogether, these data suggest that humans can adapt various movement types but the rate and extent of adaptation is not the same across movement types nor across ages.

Prism adaptation in Parkinson disease: comparing reaching to walking and freezers to non-freezers.

Visuomotor adaptation to gaze-shifting prism glasses requires recalibration of the relationship between sensory input and motor output. Healthy individuals flexibly adapt movement patterns to many external perturbations; however, individuals with cerebellar damage do not adapt movements to the same extent. People with Parkinson disease (PD) adapt normally, but exhibit reduced after-effects, which are negative movement errors following the removal of the prism glasses and are indicative of true spatial realignment. Walking is particularly affected in PD, and many individuals experience freezing of gait (FOG), an episodic interruption in walking, that is thought to have a distinct pathophysiology. Here, we examined how individuals with PD with (PD + FOG) and without (PD - FOG) FOG, along with healthy older adults, adapted both reaching and walking patterns to prism glasses. Participants completed a visually guided reaching and walking task with and without rightward-shifting prism glasses. All groups adapted at similar rates during reaching and during walking. However, overall walking adaptation rates were slower compared to reaching rates. The PD - FOG group showed smaller after-effects, particularly during walking, compared to PD + FOG, independent of adaptation magnitude. While FOG did not appear to affect characteristics of prism adaptation, these results support the idea that the distinct neural processes governing visuomotor adaptation and storage are differentially affected by basal ganglia dysfunction in PD.

Genomic and metabolic disposition of non-obese type 2 diabetic rats to increased myocardial fatty acid metabolism.

Lipotoxicity of the heart has been implicated as a leading cause of morbidity in Type 2 Diabetes Mellitus (T2DM). While numerous reports have demonstrated increased myocardial fatty acid (FA) utilization in obese T2DM animal models, this diabetic phenotype has yet to be demonstrated in non-obese animal models of T2DM. Therefore, the present study investigates functional, metabolic, and genomic differences in myocardial FA metabolism in non-obese type 2 diabetic rats. The study utilized Goto-Kakizaki (GK) rats at the age of 24 weeks. Each rat was imaged with small animal positron emission tomography (PET) to estimate myocardial blood flow (MBF) and myocardial FA metabolism. Echocardiograms (ECHOs) were performed to assess cardiac function. Levels of triglycerides (TG) and non-esterified fatty acids (NEFA) were measured in both plasma and cardiac tissues. Finally, expression profiles for 168 genes that have been implicated in diabetes and FA metabolism were measured using quantitative PCR (qPCR) arrays. GK rats exhibited increased NEFA and TG in both plasma and cardiac tissue. Quantitative PET imaging suggests that GK rats have increased FA metabolism. ECHO data indicates that GK rats have a significant increase in left ventricle mass index (LVMI) and decrease in peak early diastolic mitral annular velocity (E') compared to Wistar rats, suggesting structural remodeling and impaired diastolic function. Of the 84 genes in each the diabetes and FA metabolism arrays, 17 genes in the diabetes array and 41 genes in the FA metabolism array were significantly up-regulated in GK rats. Our data suggest that GK rats' exhibit increased genomic disposition to FA and TG metabolism independent of obesity.

A PET-compatible tissue bioreactor for research, discovery, and validation of imaging biomarkers and radiopharmaceuticals: system design and proof-of-concept studies.

UNLABELLED: Research and discovery of novel radiopharmaceuticals and targets thereof generally involves initial studies in cell cultures, followed by animal studies, both of which present several inherent limitations. The objective of this work was to develop a tissue bioreactor (TBR) enabling modulation of the microenvironment and to integrate the TBR with a small-animal PET scanner to facilitate imaging biomarker research and discovery and validation of radiopharmaceuticals. METHODS: The TBR chamber is a custom-blown, water-jacketed, glass vessel enclosed in a circulating perfusion bath powered by a peristaltic pump, which is integrated within the field of view of the PET scanner. The chamber is in series with a gas exchanger and a vessel for degassing the system during filling. Dissolved oxygen/temperature probes and septa for injection or sampling are located at the inlet and outlet of the cell chamber. A pH probe is located at the chamber outlet. Effluent is collected in the fraction collector as mixed-cup samples. In addition, both medium and tissue chamber can be sampled to investigate tissue and secretory products through multiscale analysis. As a proof of concept, we studied the effects of lipids on glucose uptake using HepG2 cells. To that end, we varied the nutrient substrate environment over a period of approximately 27 d, before and after the addition of lipids, and studied the effects of pioglitazone, a peroxisome proliferator-activated receptor γ agonist, on lipid and glucose uptake. In parallel, the TBR was imaged by PET in conjunction with (11)C-palmitate in the presence and absence of lipids to characterize (11)C-palmitate uptake. RESULTS: The O2 consumption, glucose consumption, lactate production, and free fatty acid consumption and production rates were consistent in demonstrating the effects of lipids on glucose uptake. Pioglitazone exhibited improved glucose uptake within 3 d of treatment. Semiquantitative analysis suggested that lipids induced greater (11)C-palmitate uptake. CONCLUSION: The integrated TBR offers a platform to monitor and modulate the tissue microenvironment, thus facilitating tissue-specific imaging and therapeutic biomarkers of disease, identification of molecular diagnostic markers, and validation of radiopharmaceuticals in both rodent and human cell lines.

Predictors of gait speeds and the relationship of gait speeds to falls in men and women with Parkinson disease.

Gait difficulties and falls are commonly reported in people with Parkinson disease (PD). Reduction in gait speed is a major characteristic of Parkinsonian gait, yet little is known about its underlying determinants, its ability to reflect an internal reservation about walking, or its relationship to falls. To study these issues, we selected age, disease severity, and nonmotor factors (i.e., depression, quality of life, balance confidence, and exercise beliefs and attitudes) to predict self-selected (SELF), fast-as-possible (FAST), and the difference (DIFF) between these walking speeds in 78 individuals with PD. We also examined gender differences in gait speeds and evaluated how gait speeds were related to a retrospective fall report. Age, disease severity, and balance confidence were strong predictors of SELF, FAST, and, to a lesser extent, DIFF. All three parameters were strongly associated with falling. DIFF was significantly greater in men compared to women and was significantly associated with male but not female fallers. The results supported the clinical utility of using a suite of gait speed parameters to provide insight into the gait difficulties and differentiating between fallers in people with PD.

Kinetic analysis of FDG in rat liver: effect of dietary intervention on arterial and portal vein input.

INTRODUCTION: Dietary conditions may affect liver [(18)F]FDG kinetics due to arterial and portal vein (PV) input. The purpose of this study was to evaluate kinetic models of [(18)F]FDG metabolism under a wide range of dietary interventions taking into account variations in arterial (HA) and portal vein (PV) input. METHODS: The study consisted of three groups of rats maintained under different diet interventions: 12 h fasted, 24 h fasted and those fed with high fructose diet. [(15)O]H2O PET imaging was used to characterize liver flow contribution from HA and PV to the liver's dual input function (DIF). [(18)F]FDG PET imaging was used to characterize liver metabolism. Differences in [(18)F]FDG kinetics in HA, PV and liver under different diet interventions were investigated. An arterial to PV Transfer Function (TF) was optimized in all three dietary states to noninvasively estimate PV activity. Finally, two compartment 3-parameter (2C3P), two compartment 4-parameter (2C4P), two compartment 5-parameter (2C5P), and three compartment 5-parameter (3C5P) models were evaluated and compared to describe the kinetics of [(18)F]FDG in the liver across diet interventions. Sensitivity of the compartmental models to ratios of HA to PV flow fractions was further investigated. RESULTS: Differences were found in HA and PV [(18)F]FDG kinetics across 12h fasted, 24h fasted and high fructose fed diet interventions. A two exponential TF model was able to estimate portal activity in all the three diet interventions. Statistical analysis suggests that a 2C3P model configuration was adequate to describe the kinetics of [(18)F]FDG in the liver under wide ranging dietary interventions. The net influx of [(18)F]FDG was lowest in the 12h fasted group, followed by 24 h fasted group, and high fructose diet. CONCLUSIONS: A TF was optimized to non-invasively estimate PV time activity curve in different dietary states. Several kinetic models were assessed and a 2C3P model was sufficient to describe [(18)F]FDG liver kinetics despite differences in HA and PV kinetics across wide ranging dietary interventions. The observations have broader implications for the quantification of liver metabolism in metabolic disorders and cancer, among others.

Artificial tissue bioreactor (ATB) for biological and imaging applications.

Three-dimensional (3D) culture systems are increasingly applied to study tissue biology. In this work, we report on the development of an artificial tissue bioreactor (ATB) designed to simulate the 3D structure and microenvironment of tissues in vivo, with multiple avenues of sampling, including the tissue chamber, for downstream analysis. Additionally, the ATB is integrated with the microPET Focus F220 for in-vivo imaging applications. As a proof-of-concept, we characterized the effects of lipids on glucose utilization using HepG2 cells. ATB studies were performed pre- and post- therapeutic intervention with the PPAR-γ agonist pioglitazone. In parallel, Glucose Tolerance Test (GTT) is performed on media samples to assess glucose uptake by cells as a measures of insulin signaling sensitivity. Fatty acid uptake in the ATB cell chamber is measured using [(11)C]Palmitate with microPET imaging. Overall, the ATB will facilitate the use of existing and novel radiopharmaceuticals in discovery of validating and translating insights derived from ATB studies to pre-clinical animal studies, to clinical evaluation.