Full-dose whole-body PET synthesis from low-dose PET using high-efficiency denoising diffusion probabilistic model: PET consistency model.

PURPOSE: Positron Emission Tomography (PET) has been a commonly used imaging modality in broad clinical applications. One of the most important tradeoffs in PET imaging is between image quality and radiation dose: high image quality comes with high radiation exposure. Improving image quality is desirable for all clinical applications while minimizing radiation exposure is needed to reduce risk to patients. METHODS: We introduce PET Consistency Model (PET-CM), an efficient diffusion-based method for generating high-quality full-dose PET images from low-dose PET images. It employs a two-step process, adding Gaussian noise to full-dose PET images in the forward diffusion, and then denoising them using a PET Shifted-window Vision Transformer (PET-VIT) network in the reverse diffusion. The PET-VIT network learns a consistency function that enables direct denoising of Gaussian noise into clean full-dose PET images. PET-CM achieves state-of-the-art image quality while requiring significantly less computation time than other methods. Evaluation with normalized mean absolute error (NMAE), peak signal-to-noise ratio (PSNR), multi-scale structure similarity index (SSIM), normalized cross-correlation (NCC), and clinical evaluation including Human Ranking Score (HRS) and Standardized Uptake Value (SUV) Error analysis shows its superiority in synthesizing full-dose PET images from low-dose inputs. RESULTS: In experiments comparing eighth-dose to full-dose images, PET-CM demonstrated impressive performance with NMAE of 1.278 ± 0.122%, PSNR of 33.783 ± 0.824 dB, SSIM of 0.964 ± 0.009, NCC of 0.968 ± 0.011, HRS of 4.543, and SUV Error of 0.255 ± 0.318%, with an average generation time of 62 s per patient. This is a significant improvement compared to the state-of-the-art diffusion-based model with PET-CM reaching this result 12× faster. Similarly, in the quarter-dose to full-dose image experiments, PET-CM delivered competitive outcomes, achieving an NMAE of 0.973 ± 0.066%, PSNR of 36.172 ± 0.801 dB, SSIM of 0.984 ± 0.004, NCC of 0.990 ± 0.005, HRS of 4.428, and SUV Error of 0.151 ± 0.192% using the same generation process, which underlining its high quantitative and clinical precision in both denoising scenario. CONCLUSIONS: We propose PET-CM, the first efficient diffusion-model-based method, for estimating full-dose PET images from low-dose images. PET-CM provides comparable quality to the state-of-the-art diffusion model with higher efficiency. By utilizing this approach, it becomes possible to maintain high-quality PET images suitable for clinical use while mitigating the risks associated with radiation. The code is availble at https://github.com/shaoyanpan/Full-dose-Whole-body-PET-Synthesis-from-Low-dose-PET-Using-Consistency-Model.

Alterations in adolescent brain serotonin (5HT)1A, 5HT2A, and dopamine (D)2 receptor systems in a nonhuman primate model of early life adversity.

Stress affects brain serotonin (5HT) and dopamine (DA) function, and the effectiveness of 5HT and DA to regulate stress and emotional responses. However, our understanding of the long-term impact of early life adversity (ELA) on primate brain monoaminergic systems during adolescence is scarce and inconsistent. Filling this gap in the literature is critical, given that the emergence of psychopathology during adolescence has been related to deficits in these systems. Here, we use a translational nonhuman primate (NHP) model of ELA (infant maltreatment by the mother) to examine the long-term impact of ELA on adolescent 5HT1A, 5HT2A and D2 receptor systems. These receptor systems were chosen based on their involvement in stress/emotional control, as well as reward and reinforcement. Rates of maternal abuse, rejection, and infant's vocalizations were obtained during the first three postnatal months, and hair cortisol concentrations obtained at 6 months postnatal were examined as early predictors of binding potential (BP) values obtained during adolescence using positron emission tomography (PET) imaging. Maltreated animals demonstrated significantly lower 5HT1A receptor BP in prefrontal cortical areas as well as the amygdala and hippocampus, and lower 5HT2A receptor BP in striatal and prefrontal cortical areas. Maltreated animals also demonstrated significantly lower D2 BP in the amygdala. None of the behavioral and neuroendocrine measurements obtained early in life predicted any changes in BP data. Our findings suggest that early caregiving experiences regulate the development of brain 5HT and DA systems in primates, resulting in long-term effects evident during adolescence.

Acute psychological stress-induced progenitor cell mobilization and cardiovascular events.

OBJECTIVE: Certain brain activation responses to psychological stress are associated with worse outcomes in CVD patients. We hypothesized that elevated acute psychological stress, manifesting as greater activity within neural centers for emotional regulation, mobilizes CPC from the bone marrow to the peripheral blood and predicts future cardiovascular events. METHODS: In 427 patients with stable CAD undergoing a laboratory-based mental stress (MS) test, CPCs were enumerated using flow cytometry as CD34-expressing mononuclear cells (CD34+) before and 45 min after stress. Changes in brain regional blood flow with MS were measured using high resolution-positron emission tomography (HR-PET). Association between the change in CPC with MS and the risk of cardiovascular death or myocardial infarction (MI) during a 5-year follow-up period was analyzed. RESULTS: MS increased CPC counts by a mean of 150 [630] cells/mL (15%), P < 0.001. Greater limbic lobe activity, indicative of activation of emotion-regulating centers, was associated with greater CPC mobilization (P < 0.005). Using Fine and Gray models after adjustment for demographioc, clinical risk factors and medications use, greater CPC mobilization was associated with a higher adjusted risk of adverse events; a rise of 1000 cells/mL was associated with a 50% higher risk of cardiovascular death/MI [hazards ratio, 1.5, 95% confidence interval, 1.1-2.2). CONCLUSION: Greater limbic lobe activity, brain areas involved in emotional regulation, is associated with MS-induced CPC mobilization. This mobilization isindependently associated with cardiovascular events. These findings provide novel insights into mechanisms through which psychological stressors modulate cardiovascular risk.

Neural correlates of PTSD in women with childhood sexual abuse with and without PTSD and response to paroxetine treatment: A placebo-controlled, double-blind trial.

Objective: Childhood sexual abuse is the leading cause of posttraumatic stress disorder (PTSD) in women, and is a prominent cause of morbidity and loss of function for which limited treatments are available. Understanding the neurobiology of treatment response is important for developing new treatments. The purpose of this study was to assess neural correlates of personalized traumatic memories in women with childhood sexual abuse with and without PTSD, and to assess response to treatment. Methods: Women with childhood sexual abuse with (N = 28) and without (N = 17) PTSD underwent brain imaging with High-Resolution Positron Emission Tomography scanning with radiolabeled water for brain blood flow measurements during exposure to personalized traumatic scripts and memory encoding tasks. Women with PTSD were randomized to paroxetine or placebo followed by three months of double-blind treatment and repeat imaging with the same protocol. Results: Women with PTSD showed decreases in areas involved in the Default Mode Network (DMN), a network of brain areas usually active when the brain is at rest, hippocampus and visual processing areas with exposure to traumatic scripts at baseline while women without PTSD showed increased activation in superior frontal gyrus and other areas (p < 0.005). Treatment of women with PTSD with paroxetine resulted in increased anterior cingulate activation and brain areas involved in the DMN and visual processing with scripts compared to placebo (p < 0.005). Conclusion: PTSD related to childhood sexual abuse in women is associated with alterations in brain areas involved in memory and the stress response and treatment with paroxetine results in modulation of these areas.

Sex influences the effects of social status on socioemotional behavior and serotonin neurochemistry in rhesus monkeys.

BACKGROUND: Despite observed sex differences in the prevalence of stress-related psychiatric conditions, most preclinical and translational studies have only included male subjects. Therefore, it has not been possible to effectively assess how sex interacts with other psychosocial risk factors to impact the etiology and maintenance of stress-related psychopathology. One psychosocial factor that interacts with sex to impact risk for stress-related behavioral and physiological deficits is social dominance. The current study was designed to assess sex differences in the effects of social status on socioemotional behavior and serotonin neurochemistry in socially housed rhesus monkeys. We hypothesized that sex and social status interact to influence socioemotional behaviors as well as serotonin 1A receptor binding potential (5HT1AR-BP) in regions of interest (ROIs) implicated in socioemotional behavior. METHODS: Behavioral observations were conducted in gonadally intact adult female (n = 14) and male (n = 13) rhesus monkeys. 5HT1AR-BP was assessed via positron emission tomography using 4-(2'-Methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p[18F]fluorobenzamido]ethylpiperazine ([18F]MPPF). RESULTS: Aggression emitted was greater in dominant compared to subordinate animals, regardless of sex. Submission emitted was significantly greater in subordinate versus dominant animals and greater in females than males. Affiliative behaviors emitted were not impacted by sex, status, or their interaction. Anxiety-like behavior emitted was significantly greater in females than in males regardless of social status. Hypothalamic 5HT1AR-BP was significantly greater in females than in males, regardless of social status. 5HT1AR-BP in the dentate gyrus of the hippocampus was significantly impacted by a sex by status interaction whereby 5HT1AR-BP in the dentate gyrus was greater in dominant compared to subordinate females but was not different between dominant and subordinate males. There were no effects of sex, status, or their interaction on 5HT1AR-BP in the DRN and in the regions of the PFC studied. CONCLUSIONS: These data have important implications for the treatment of stress-related behavioral health outcomes, as they suggest that sex and social status are important factors to consider in the context of serotonergic drug efficacy.

Females are more likely to suffer from stress-related conditions that impact socioemotional behavior compared to males. One thing that influences how sex impacts stress-related health problems is social dominance. We examined whether there are sex differences in the effects of social dominance on socioemotional behavior in socially housed rhesus monkeys. Because the neurotransmitter serotonin is important for socioemotional behavior, we also looked at the levels of the 5HT1AR receptor using neuroimaging. Aggression was greater in dominant compared to subordinate animals, and submission was significantly greater in subordinate versus dominant animals and greater in females than males. Anxiety and levels of 5HT1AR in the hypothalamus were significantly greater in females than in males. 5HT1AR in the hippocampus was greater in dominant compared to subordinate females but was not different between dominant and subordinate males. Overall, these data are important for the treatment of stress-related behavioral health outcomes because suggest that sex and social dominance are important factors to consider in the context of how effective drugs targeting the serotonin system are for treating stress-related behavioral health conditions.

Concise and Scalable Radiosynthesis of (+)-[18F]MDL100907 as a Serotonin 5-HT2A Receptor Antagonist for PET.

5-Hydroxytryptamine (5-HT2A) receptors play an important role in several psychiatric disorders. In order to investigate the serotonin (5-HT) receptor in vivo, reliable syntheses are required for positron emission tomography (PET) 5-HT radioligands. Owing to the excellent in vivo properties of [18F]MDL100907 for PET, there has been great interest to develop a novel synthetic route for [18F]MDL100907. Here, we report a highly efficient, scalable, and expedient synthesis for [18F]MDL100907. The radiofluorination was performed on a 18F-labeling boron pinacol ester precursor, which is synthesized using the Liebeskind-Srogl cross-coupling reaction as a key step. Our method is practically more suitable to employ late-stage Cu-mediated radiofluorination and facilitate the production of the [18F]MDL100907 radioligand in excellent decay-corrected RCY of 32 ± 10% (n = 7) within 60 min. We prepared [18F]MDL100907 in high molar activity (2.1 Ci/µmol) and compared it to [11C]MDL100907 in the brain of a nonhuman primate.

Transcutaneous vagal nerve stimulation modulates stress-induced plasma ghrelin levels: A double-blind, randomized, sham-controlled trial.

BACKGROUND: Transcutaneous cervical vagus nerve stimulation (tcVNS) has emerged as a potential treatment strategy for patients with stress-related psychiatric disorders. Ghrelin is a hormone that has been postulated to be a biomarker of stress. While the mechanisms of action of tcVNS are unclear, we hypothesized that tcVNS reduces the levels of ghrelin in response to stress. METHODS: Using a randomized double-blind approach, we studied the effects of tcVNS on ghrelin levels in individuals with a history of exposure to traumatic stress. Participants received either sham (n = 29) or active tcVNS (n = 26) after exposure to acute personalized traumatic script stress and mental stress challenges (public speech, mental arithmetic) over a three day period. RESULTS: There were no significant differences in the levels of ghrelin between the tcVNS and sham stimulation groups at either baseline or in the absence of trauma scripts. However, tcVNS in conjunction with personalized traumatic scripts resulted in lower ghrelin levels compared to the sham stimulation group (265.2 ± 143.6 pg/ml vs 478.7 ± 349.2 pg/ml, P = 0.01). Additionally, after completing the public speaking and mental arithmetic tests, ghrelin levels were found to be lower in the group receiving tcVNS compared to the sham group (293.3 ± 102.4 pg/ml vs 540.3 ± 203.9 pg/ml, P = 0.009). LIMITATIONS: Timing of ghrelin measurements, and stimulation of only left vagus nerve. CONCLUSION: tcVNS decreases ghrelin levels in response to various stressful stimuli. These findings are consistent with a growing literature that tcVNS modulates hormonal and autonomic responses to stress.

A Pilot Study of Neurobiological Mechanisms of Stress and Cardiovascular Risk.

Objective: Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk. Methods: Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [18F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress. Results: Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004). Conclusions: These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients.

Quality management, quality assurance, and quality control in medical physics.

The historic and ongoing evolution of the practice, technology, terminology, and implementation of programs related to quality in the medical radiological professions has given rise to the interchangeable use of the terms Quality Management (QM), Quality Assurance (QA), and Quality Control (QC) in the vernacular. This White Paper aims to provide clarification of QM, QA, and QC in medical physics context and guidance on how to use these terms appropriately in American College of Radiology (ACR) Practice Parameters and Technical Standards, generalizable to other guidance initiatives. The clarification of these nuanced terms in the radiology, radiation oncology, and nuclear medicine environments will not only boost the comprehensibility and usability of the Medical Physics Technical Standards and Practice Parameters, but also provide clarity and a foundation for ACR's clinical, physician-led Practice Parameters, which also use these important terms for monitoring equipment performance for safety and quality. Further, this will support the ongoing development of the professional practice of clinical medical physics by providing a common framework that distinguishes the various types of responsibilities borne by medical physicists and others in the medical radiological environment. Examples are provided of how QM, QA, and QC may be applied in the context of ACR Practice Parameters and Technical Standards.

Left Ventricular Strain from Myocardial Perfusion PET Imaging: Method Development and Comparison to 2-Dimensional Echocardiography.

This study aimed to develop a measure of longitudinal, radial, and circumferential myocardial strain at rest and regadenoson during pharmacologic stress using 82Rb PET electrocardiography-gated myocardial perfusion imaging (MPI). Methods: We retrospectively identified 80 patients who underwent rest and regadenoson-stress CT attenuation-corrected 82Rb PET and had a standard resting transthoracic echocardiogram (TTE) with global longitudinal strain (GLS) analysis within 3 mo. A method was developed to compute longitudinal, radial, and circumferential strain from PET MPI at stress and rest. PET MPI-derived strain and left ventricular function were compared with resting TTE measures as the clinical reference standard. Interobserver agreement of PET MPI strain and left ventricular ejection fraction processing was reported. Results: Longitudinal strain assessed with resting TTE GLS showed good correlation with PET MPI at stress (r = 0.68, P < 0.001) and rest (r = 0.58, P < 0.001). Resting TTE GLS also correlated with PET MPI radial strain at stress (r = -0.70, P < 0.001) and rest (r = -0.59, P < 0.001) and circumferential strain at stress (r = 0.67, P < 0.001) and rest (r = 0.69, P < 0.001). The left ventricular ejection fraction showed good correlation between resting TTE and PET MPI at stress (r = 0.83, P < 0.001) and rest (r = 0.80, P < 0.001). Bland-Altman analysis indicated positive bias of TTE GLS compared with PET MPI longitudinal strain at stress (mean difference = 5.1%, 95% CI = [-2.5, 12.7]) and rest (mean difference = 4.2%, 95% CI = [-4.3, 12.8]). Reproducibility of PET MPI longitudinal strain showed good agreement at stress (concordance correlation coefficient = 0.73, P < 0.001) and rest (concordance correlation coefficient = 0.74, P < 0.001), with Bland-Altman analysis showing a small bias in the longitudinal direction at stress (mean difference = -0.2%) and rest (mean difference = -1.0%). Conclusion: Strain measured with PET MPI using an automated technique correlated well with resting GLS strain obtained by TTE, and the measure is reproducible. Strain from PET MPI should be investigated further to establish reference ranges and assess its value in routine clinical practice.

Safety and biomarker effects of candesartan in non-hypertensive adults with prodromal Alzheimer's disease.

Observational studies suggest that angiotensin receptor blockers in hypertensive adults are associated with lower post-mortem indicators of Alzheimer's disease pathology. Candesartan, an angiotensin receptor blocker, has a positive cognitive effect in mild cognitive impairment with hypertension. However, its safety and effects in non-hypertensive individuals with Alzheimer's disease are unclear. This is the first double-blind randomized placebo-controlled trial aimed to assess safety and effects of 1-year therapy of candesartan on biomarkers and clinical indicators of Alzheimer's disease in non-hypertensive individuals with biomarker-confirmed prodromal Alzheimer's disease. Seventy-seven non-hypertensive participants 50 years or older (mean age: 68.1 years; 62% women; 20% African American) with mild cognitive impairment and biomarker confirmed Alzheimer's disease were randomized to escalating doses of once daily oral candesartan (up to 32 mg) or matched placebo. Main outcomes included safety and tolerability of candesartan, cerebrospinal fluid biomarkers (amyloid-ß42, amyloid-ß40, total tau and phospho-tau). Additional exploratory outcomes included PET imaging (Pittsburgh Compound-B (11C-PiB) and 18F-flortaucipir), brain MRI (structural and connectivity measures) and cognitive functioning. Analyses used intention-to-treat approach with group comparisons of safety measures using Chi-square test, and repeated measures mixed effects models were used to assess candesartan effects on main and exploratory outcomes (ClinicalTrials.gov, NCT02646982). Candesartan was found to be safe with no significant difference in safety measures: symptoms of hypotension, renal failure or hyperkalemia. Candesartan was also found to be associated with increases in cerebrospinal fluid Aß40 (between-group mean difference: 1211.95 pg/ml, 95% confidence interval: 313.27, 2110.63) and Aß42 (49.51 pg/ml, 95% confidence interval: -98.05, -0.98) reflecting lower brain amyloid accumulation. Candesartan was associated with decreased 11C-PiB in the parahippocampal region (-0.1104, 95% confidence interval: -0.19, -0.029) which remained significant after false discovery rate correction, and with an increase in functional network connectivity in the subcortical networks. Candesartan was further associated with improved executive function (Trail Making Test Part B) performance (-11.41 s, 95% confidence interval: -11.94, -10.89) and trended for an improved global cognitive functioning reflected by a composite cognitive score (0.002, 95% confidence interval: -0.0002, 0.005). We did not observe significant effects on tau levels, hippocampal volume or other cognitive measures (memory or clinical dementia rating scale-sum of boxes). In conclusion, among non-hypertensive prodromal Alzheimer's disease, candesartan is safe and likely decreases brain amyloid biomarkers, enhances subcortical brain connectivity and has favourable cognitive effects. These findings suggest that candesartan may have an important therapeutic role in Alzheimer's disease, and warrant further investigation given the lack of clear treatment options for this devastating illness.

Obstructive sleep apnea, myocardial perfusion and myocardial blood flow: A study of older male twins.

BACKGROUND: Obstructive sleep apnea (OSA) has been associated with incidence of cardiovascular disease and with nocturnal angina, but evidence of a link with coronary atherosclerosis and myocardial ischemia is limited and previous studies may have been affected by selection bias or unmeasured confounding factors. METHODS: We performed overnight polysomnography in 178 older male twins. The Apnea/Hypopnea Index (AHI) was calculated to assess OSA from the overnight sleep evaluation. AHI ≥15 was used as indicator of moderate/severe OSA. The following day, twins underwent myocardial perfusion imaging with [82Rb]-chloride positron emission tomography. Quantitative and semiquantitative measures of myocardial perfusion and absolute myocardial blood flow were obtained. RESULTS: The mean age was 68 years and 40% of the sample had an AHI≥15, which indicates moderate to severe OSA. Abnormal myocardial perfusion, both with stress and at rest, was more common in twins with elevated AHI. After adjusting for clinical, lifestyle and behavioral factors, and previous history of cardiovascular disease, twins with AHI ≥15 had 3.6 higher odds (95% CI, 1.5-8.9) of an abnormal total severity score, defined as a score ≥100, and for each 5-point increment in AHI, the odds of abnormality increased by 20% (95% CI, 7%-34%). Twin pairs where both twins had OSA exhibited the greatest risk. There were no differences in measures of ischemia and absolute myocardial blood flow and flow reserve by AHI status. CONCLUSIONS: OSA is associated with myocardial perfusion abnormalities that suggest prior subclinical myocardial scarring or infarction. Early environmental factors that affect both twins equally may play a role and should be further explored.

Leveraging Accelerometry as a Prognostic Indicator for Increase in Opioid Withdrawal Symptoms.

Treating opioid use disorder (OUD) is a significant healthcare challenge in the United States. Remaining abstinent from opioids is challenging for individuals with OUD due to withdrawal symptoms that include restlessness. However, to our knowledge, studies of acute withdrawal have not quantified restlessness using involuntary movements. We hypothesized that wearable accelerometry placed mid-sternum could be used to detect withdrawal-related restlessness in patients with OUD. To study this, 23 patients with OUD undergoing active withdrawal participated in a protocol involving wearable accelerometry, opioid cues to elicit craving, and non-invasive Vagal Nerve Stimulation (nVNS) to dampen withdrawal symptoms. Using accelerometry signals, we analyzed how movements correlated with changes in acute withdrawal severity, measured by the Clinical Opioid Withdrawal Scale (COWS). Our results revealed that patients demonstrating sinusoidal-i.e., predominantly single-frequency oscillation patterns in their motion almost exclusively demonstrated an increase in the COWS, and a strong relationship between the maximum power spectral density and increased withdrawal over time, measured by the COWS (R = 0.92, p = 0.029). Accelerometry may be used in an ambulatory setting to indicate the increased intensity of a patient's withdrawal symptoms, providing an objective, readily-measurable marker that may be captured ubiquitously.

Clinically viable myocardial CCTA segmentation for measuring vessel-specific myocardial blood flow from dynamic PET/CCTA hybrid fusion.

BACKGROUND: Positron emission tomography (PET)-derived LV MBF quantification is usually measured in standard anatomical vascular territories potentially averaging flow from normally perfused tissue with those from areas with abnormal flow supply. Previously we reported on an image-based tool to noninvasively measure absolute myocardial blood flow at locations just below individual epicardial vessel to help guide revascularization. The aim of this work is to determine the robustness of vessel-specific flow measurements (MBFvs) extracted from the fusion of dynamic PET (dPET) with coronary computed tomography angiography (CCTA) myocardial segmentations, using flow measured from the fusion with CCTA manual segmentation as the reference standard. METHODS: Forty-three patients' 13NH3 dPET, CCTA image datasets were used to measure the agreement of the MBFvs profiles after the fusion of dPET data with three CCTA anatomical models: (1) a manual model, (2) a fully automated segmented model and (3) a corrected model, where major inaccuracies in the automated segmentation were briefly edited. Pairwise accuracy of the normality/abnormality agreement of flow values along differently extracted vessels was determined by comparing, on a point-by-point basis, each vessel's flow to corresponding vessels' normal limits using Dice coefficients (DC) as the metric. RESULTS: Of the 43 patients CCTA fully automated mask models, 27 patients' borders required manual correction before dPET/CCTA image fusion, but this editing process was brief (2-3 min) allowing a 100% success rate of extracting MBFvs in clinically acceptable times. In total, 124 vessels were analyzed after dPET fusion with the manual and corrected CCTA mask models yielding 2225 stress and 2122 rest flow values. Forty-seven vessels were analyzed after fusion with the fully automatic masks producing 840 stress and 825 rest flow samples. All DC coefficients computed globally or by territory were ≥ 0.93. No statistical differences were found in the normal/abnormal flow classifications between manual and corrected or manual and fully automated CCTA masks. CONCLUSION: Fully automated and manually corrected myocardial CCTA segmentation provides anatomical masks in clinically acceptable times for vessel-specific myocardial blood flow measurements using dynamic PET/CCTA image fusion which are not significantly different in flow accuracy and within clinically acceptable processing times compared to fully manually segmented CCTA myocardial masks.

Robust Estimation of Respiratory Variability Uncovers Correlates of Limbic Brain Activity and Transcutaneous Cervical Vagus Nerve Stimulation in the Context of Traumatic Stress.

OBJECTIVE: Variations in respiration patterns are a characteristic response to distress due to underlying neurorespiratory couplings. Yet, no work to date has quantified respiration pattern variability (RPV) in the context of traumatic stress and studied its functional neural correlates - this analysis aims to address this gap. METHODS: Fifty human subjects with prior traumatic experiences (24 with posttraumatic stress disorder (PTSD)) completed a ∼3-hr protocol involving personalized traumatic scripts and active/sham (double-blind) transcutaneous cervical vagus nerve stimulation (tcVNS). High-resolution positron emission tomography functional neuroimages, electrocardiogram (ECG), and respiratory effort (RSP) data were collected during the protocol. Supplementing the RSP signal with ECG-derived respiration for quality assessment and timing extraction, RPV metrics were quantified and analyzed. Specifically, correlation analyses were performed using neuroactivity in selected limbic regions, and responses to active and sham tcVNS were compared. RESULTS: The single-lag unscaled autocorrelation of respiration rate correlated negatively with left amygdala activity and positively with right rostromedial prefrontal cortex (rmPFC) activity for non-PTSD; it also correlated negatively with left and right insulae activity and positively with right rmPFC activity for PTSD. The single-lag unscaled autocorrelation of expiration time was greater following active stimulation for non-PTSD. CONCLUSION: Quantifying RPV is of demonstrable importance to assessing trauma-induced changes in neural function and tcVNS effects on respiratory physiology. SIGNIFICANCE: This is the first demonstration of RPV's pertinence to traumatic stress- and tcVNS-induced neurorespiratory responses. The open-source processing pipeline elucidated herein uniquely includes both RSP and ECG-derived respiration signals for quality assessment, timing estimation, and RPV extraction.

Determination of [N-13]-ammonia extraction fraction in patients with coronary artery disease by calibration to invasive coronary and fractional flow reserve.

BACKGROUND: This study presents a new extraction fraction (EF) model based on physiological measures of invasive coronary flow reserve (CFR) and fractional flow reserve (FFR) in patients with suspected coronary artery disease (CAD) and normal index microcirculatory resistance (IMR). To ascertain the clinical relevance of the new EFs, flow measurements using the newly patient-determined EFs were compared to flow measurements using traditional animal-determined EFs. METHODS: 39 patients were retrospectively selected that included a total of 91 vascular territories with invasive coronary angiography physiological measures. [N-13]-ammonia dynamic rest/adenosine-stress PET imaging was conducted in all patients and absolute myocardial flow was estimated using four published compartmental models. The extraction fraction during hyperemic flow was iteratively estimated by maximizing the agreement between invasive CFR and FFR with the non-invasive analogs myocardial flow reserve (MFR) and relative flow reserve (RFR) at similar physiological states, respectively. RESULTS: Using the new patient-determined EFs, agreement between CFR vs MFR for Model 1 and 2 was moderate and poor for Model 3 and 4. All models showed moderate agreement for FFR vs RFR. When using published models of animal-determined EFs, agreement between CFR vs MFR remained moderate for Model 1 and 2, and poor for Model 3 and 4. Similarly, all models showed moderate agreement for FFR vs RFR using animal-determined EF values. None of the observed differences were statistically significant. CONCLUSIONS: Flow measurements using extraction fraction correction for [N-13]-ammonia based on calibration to invasive intracoronary angiography physiological measures in patients with CAD were not discordant from those reported in the literature. Either patient-determined or traditional animal-determined EF correction, when used with the appropriate flow model, yields moderate agreement with invasive measurements of coronary flow reserve and fractional flow reserve.

Synthesis and Evaluation of [11C]7-Halogen-2-Phenyl Isoindolone Derivatives: Potential PET Radioligands for in vivo Imaging of 5-HT2 C Receptors.

The serotonin 5-HT2 C receptor (5-HT2 C R) is abundantly expressed throughout the central nervous system, and involved in a variety of neuroendocrine and neurobehavioral processes. The development of a selective radioligand that will enable in vivo imaging and quantification of 5-HT2 C R densities represents a significant technological advancement in understanding both the normal function and pathophysiology of the 5-HT2 C R. Four 7-halogen-2-phenyl isoindolones (7-F, Cl, Br, I) were synthesized and displayed high affinities for 5-HT2 C R and high selectivity over 5-HT2 A and 5-HT2 B . [11C]7-Chloro-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (6) and [11C]7-iodo-2-[4-methoxy-3-[2-(4-methylpiperidin-1-yl)ethoxy]phenyl]isoindolin-1-one (9) were synthesized in high radiochemical yield of 37-44% [n = 10, decay corrected from end of (11C)CH3I synthesis] with high radiochemical purity via O-methylation with [11C]CH3I, respectively. MicroPET imaging studies in male rats with or without 5-HT2 C antagonist SB-242084 showed that [11C]6 and [11C]9 display specific bindings to 5-HT2 C R in the choroid plexus and hippocampus. In vivo microPET brain imaging studies in rhesus monkeys demonstrated that [11C]6 and [11C]9 exhibit excellent blood-brain barrier penetration. The contrast of bindings to the choroid plexus and hippocampus compared to the cerebellum peaked at 2.7 and 1.6, respectively, for [11C]6, and 3.7 and 2.7, respectively, for [11C]9, which were reduced by administration of a dose of SB-242084. Our results support the candidacy of [11C]6 and [11C]9 for further study as radioligands for in vivo quantitation of 5-HT2 C sites by PET.