Enhancing adaptive proton therapy through CBCT images: Synthetic head and neck CT generation based on 3D vision transformers.

BACKGROUND: Proton therapy is a form of radiotherapy commonly used to treat various cancers. Due to its high conformality, minor variations in patient anatomy can lead to significant alterations in dose distribution, making adaptation crucial. While cone-beam computed tomography (CBCT) is a well-established technique for adaptive radiation therapy (ART), it cannot be directly used for adaptive proton therapy (APT) treatments because the stopping power ratio (SPR) cannot be estimated from CBCT images. PURPOSE: To address this limitation, Deep Learning methods have been suggested for converting pseudo-CT (pCT) images from CBCT images. In spite of convolutional neural networks (CNNs) have shown consistent improvement in pCT literature, there is still a need for further enhancements to make them suitable for clinical applications. METHODS: The authors introduce the 3D vision transformer (ViT) block, studying its performance at various stages of the proposed architectures. Additionally, they conduct a retrospective analysis of a dataset that includes 259 image pairs from 59 patients who underwent treatment for head and neck cancer. The dataset is partitioned into 80% for training, 10% for validation, and 10% for testing purposes. RESULTS: The SPR maps obtained from the pCT using the proposed method present an absolute relative error of less than 5% from those computed from the planning CT, thus improving the results of CBCT. CONCLUSIONS: We introduce an enhanced ViT3D architecture for pCT image generation from CBCT images, reducing SPR error within clinical margins for APT workflows. The new method minimizes bias compared to CT-based SPR estimation and dose calculation, signaling a promising direction for future research in this field. However, further research is needed to assess the robustness and generalizability across different medical imaging applications.

A case study of medical image software evolution and its impact in the medical imaging community.

Objective: We present the evolution of medical imaging software and its impact on the medical imaging community through the study of four open-source image analysis software platforms: 3D Slicer, FreeSurfer, FSL, and SPM. Materials and methods: We have studied the impact of these software tools over time, measured by the number of scientific citations. Additionally, we have also studied the source code evolution by measuring the lines of code and the tarball size of the stable releases and the changes in programming languages. Results and discussion: The rising number of related scientific publications confirms the popularity of these software tools in the research community, albeit some differences can be observed in the popularity of the tools. Moreover, we demonstrate that source code has evolved to modernize and optimize, at least partially thanks to the collaboration and code sharing with the user community. Furthermore, this evolution reveals an increased use of higher-level programming languages and meta-languages. Conclusions: The study of four open-source packages has revealed certain patterns in the evolution of medical imaging software and their impact on the medical image community. Further analyses and complementary metrics are suggested.

Material decomposition maps based calibration of dual energy CT scanners for proton therapy planning: a phantom study.

We introduce a new calibration method for dual energy CT (DECT) based on material decomposition (MD) maps, specifically iodine and water MD maps. The aim of this method is to provide the first DECT calibration based on MD maps. The experiments were carried out using a general electric (GE) revolution CT scanner with ultra-fast kV switching and used a density phantom by GAMMEX for calibration and evaluation. The calibration process involves several steps. First, we tested the ability of MD values to reproduce Hounsfield unit (HU) values of single energy CT (SECT) acquisitions and it was found that the errors were below 1%, validating their use for HU reproduction. Next, the different definitions of computedZvalues were compared and the robustness of the approach based on the materials' composition was confirmed. Finally, the calibration method was compared with a previous method by Bourqueet al, providing a similar level of accuracy and superior performance in terms of precision. Overall, this novel DECT calibration method offers improved accuracy and reliability in determining tissue-specific physical properties. The resulting maps can be valuable for proton therapy treatments, where precise dose calculations and accurate tissue differentiation are crucial for optimal treatment planning and delivery.

[ 11 C]-PBR28 positron emission tomography signal as an imaging marker of joint inflammation in knee osteoarthritis.

ABSTRACT: Although inflammation is known to play a role in knee osteoarthritis (KOA), inflammation-specific imaging is not routinely performed. In this article, we evaluate the role of joint inflammation, measured using [ 11 C]-PBR28, a radioligand for the inflammatory marker 18-kDa translocator protein (TSPO), in KOA. Twenty-one KOA patients and 11 healthy controls (HC) underwent positron emission tomography/magnetic resonance imaging (PET/MRI) knee imaging with the TSPO ligand [ 11 C]-PBR28. Standardized uptake values were extracted from regions-of-interest (ROIs) semiautomatically segmented from MRI data, and compared across groups (HC, KOA) and subgroups (unilateral/bilateral KOA symptoms), across knees (most vs least painful), and against clinical variables (eg, pain and Kellgren-Lawrence [KL] grades). Overall, KOA patients demonstrated elevated [ 11 C]-PBR28 binding across all knee ROIs, compared with HC (all P 's < 0.005). Specifically, PET signal was significantly elevated in both knees in patients with bilateral KOA symptoms (both P 's < 0.01), and in the symptomatic knee ( P < 0.05), but not the asymptomatic knee ( P = 0.95) of patients with unilateral KOA symptoms. Positron emission tomography signal was higher in the most vs least painful knee ( P < 0.001), and the difference in pain ratings across knees was proportional to the difference in PET signal ( r = 0.74, P < 0.001). Kellgren-Lawrence grades neither correlated with PET signal (left knee r = 0.32, P = 0.19; right knee r = 0.18, P = 0.45) nor pain ( r = 0.39, P = 0.07). The current results support further exploration of [ 11 C]-PBR28 PET signal as an imaging marker candidate for KOA and a link between joint inflammation and osteoarthritis-related pain severity.

Neuroimmune activation and increased brain aging in chronic pain patients after the COVID-19 pandemic onset.

The COVID-19 pandemic has exerted a global impact on both physical and mental health, and clinical populations have been disproportionally affected. To date, however, the mechanisms underlying the deleterious effects of the pandemic on pre-existing clinical conditions remain unclear. Here we investigated whether the onset of the pandemic was associated with an increase in brain/blood levels of inflammatory markers and MRI-estimated brain age in patients with chronic low back pain (cLBP), irrespective of their infection history. A retrospective cohort study was conducted on 56 adult participants with cLBP (28 'Pre-Pandemic', 28 'Pandemic') using integrated Positron Emission Tomography/ Magnetic Resonance Imaging (PET/MRI) and the radioligand [11C]PBR28, which binds to the neuroinflammatory marker 18 kDa Translocator Protein (TSPO). Image data were collected between November 2017 and January 2020 ('Pre-Pandemic' cLBP) or between August 2020 and May 2022 ('Pandemic' cLBP). Compared to the Pre-Pandemic group, the Pandemic patients demonstrated widespread and statistically significant elevations in brain TSPO levels (P =.05, cluster corrected). PET signal elevations in the Pandemic group were also observed when 1) excluding 3 Pandemic subjects with a known history of COVID infection, or 2) using secondary outcome measures (volume of distribution -VT- and VT ratio - DVR) in a smaller subset of participants. Pandemic subjects also exhibited elevated serum levels of inflammatory markers (IL-16; P <.05) and estimated BA (P <.0001), which were positively correlated with [11C]PBR28 SUVR (r's ≥ 0.35; P's < 0.05). The pain interference scores, which were elevated in the Pandemic group (P <.05), were negatively correlated with [11C]PBR28 SUVR in the amygdala (r = -0.46; P<.05). This work suggests that the pandemic outbreak may have been accompanied by neuroinflammation and increased brain age in cLBP patients, as measured by multimodal imaging and serum testing. This study underscores the broad impact of the pandemic on human health, which extends beyond the morbidity solely mediated by the virus itself.

Thalamic neurometabolite alterations in chronic low back pain: a common phenomenon across musculoskeletal pain conditions?

ABSTRACT: Recently, we showed that patients with knee osteoarthritis (KOA) demonstrate alterations in the thalamic concentrations of several metabolites compared with healthy controls: higher myo-inositol (mIns), lower N-acetylaspartate (NAA), and lower choline (Cho). Here, we evaluated whether these metabolite alterations are specific to KOA or could also be observed in patients with a different musculoskeletal condition, such as chronic low back pain (cLBP). Thirty-six patients with cLBP and 20 healthy controls were scanned using 1 H-magnetic resonance spectroscopy (MRS) and a PRESS (Point RESolved Spectroscopy) sequence with voxel placement in the left thalamus. Compared with healthy controls, patients with cLBP demonstrated lower absolute concentrations of NAA ( P = 0.0005) and Cho ( P < 0.05) and higher absolute concentrations of mIns ( P = 0.01) when controlling for age, as predicted by our previous work in KOA. In contrast to our KOA study, mIns levels in this population did not significantly correlate with pain measures (eg, pain severity or duration). However, exploratory analyses revealed that NAA levels in patients were negatively correlated with the severity of sleep disturbance ( P < 0.01), which was higher in patients compared with healthy controls ( P < 0.001). Additionally, also in patients, both Cho and mIns levels were positively correlated with age ( P < 0.01 and P < 0.05, respectively). Altogether, these results suggest that thalamic metabolite changes may be common across etiologically different musculoskeletal chronic pain conditions, including cLBP and KOA, and may relate to symptoms often comorbid with chronic pain, such as sleep disturbance. The functional and clinical significance of these brain changes remains to be fully understood.

Assessing the potential anti-neuroinflammatory effect of minocycline in chronic low back pain: Protocol for a randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Both preclinical studies, and more recent clinical imaging studies, suggest that glia-mediated neuroinflammation may be implicated in chronic pain, and therefore might be a potential treatment target. However, it is currently unknown whether modulating neuroinflammation effectively alleviates pain in humans. This trial tests the hypothesis that minocycline, an FDA-approved tetracycline antibiotic and effective glial cell inhibitor in animals, reduces neuroinflammation and may reduce pain symptoms in humans with chronic low back pain. METHODS AND ANALYSIS: This study is a randomized, double-blind, placebo-controlled clinical trial. Subjects, aged 18-75, with a confirmed diagnosis of chronic (≥ six months) low back pain (cLBP) and a self-reported pain rating of at least four out of ten (for at least half of the days during an average week) are enrolled via written, informed consent. Eligible subjects are randomized to receive a 14-day course of either active drug (minocycline) or placebo. Before and after treatment, subjects are scanned with integrated Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) using [11C]PBR28, a second-generation radiotracer for the 18 kDa translocator protein (TSPO), which is highly expressed in glial cells and thus a putative marker of neuroinflammation. Pain levels are evaluated via daily surveys, collected seven days prior to the start of medication, and throughout the 14 days of treatment. General linear models will be used to assess pain levels and determine the treatment effect on brain (and spinal cord) TSPO signal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03106740).

Development of a Super-Resolution Scheme for Pediatric Magnetic Resonance Brain Imaging Through Convolutional Neural Networks.

Pediatric medical imaging represents a real challenge for physicians, as children who are patients often move during the examination, and it causes the appearance of different artifacts in the images. Thus, it is not possible to obtain good quality images for this target population limiting the possibility of evaluation and diagnosis in certain pathological conditions. Specifically, magnetic resonance imaging (MRI) is a technique that requires long acquisition times and, therefore, demands the use of sedation or general anesthesia to avoid the movement of the patient, which is really damaging in this specific population. Because ALARA (as low as reasonably achievable) principles should be considered for all imaging studies, one of the most important reasons for establishing novel MRI imaging protocols is to avoid the harmful effects of anesthesia/sedation. In this context, ground-breaking concepts and novel technologies, such as artificial intelligence, can help to find a solution to these challenges while helping in the search for underlying disease mechanisms. The use of new MRI protocols and new image acquisition and/or pre-processing techniques can aid in the development of neuroimaging studies for children evaluation, and their translation to pediatric populations. In this paper, a novel super-resolution method based on a convolutional neural network (CNN) in two and three dimensions to automatically increase the resolution of pediatric brain MRI acquired in a reduced time scheme is proposed. Low resolution images have been generated from an original high resolution dataset and used as the input of the CNN, while several scaling factors have been assessed separately. Apart from a healthy dataset, we also tested our model with pathological pediatric MRI, and it successfully recovers the original image quality in both visual and quantitative ways, even for available examples of dysplasia lesions. We hope then to establish the basis for developing an innovative free-sedation protocol in pediatric anatomical MRI acquisition.

Intracranial Virotherapy for a Canine Hemangioma.

Intracranial hemangiomas are rare neoplastic lesions in dogs that usually appear with life-threatening symptoms. The treatment of choice is tumor resection; however, complete resection is rarely achieved. The patient's prognosis therefore usually worsens due to tumor progression, and adjuvant treatments are required to control the disease. Oncolytic viruses are an innovative approach that lyses the tumor cells and induces immune responses. Here, we report the intratumoral inoculation of ICOCAV15 (an oncolytic adenovirus) in a canine intracranial hemangioma, as adjuvant treatment for incomplete tumor resection. The canine patient showed no side effects, and the tumor volume decreased over the 12 months after the treatment, as measured by magnetic resonance imaging using volumetric criteria. When progressive disease was detected at month 18, a new dose of ICOCAV15 was administered. The patient died 31.9 months after the first inoculation of the oncolytic adenovirus. Furthermore, tumor-infiltrated immune cells increased in number after the viral administrations, suggesting tumor microenvironment activation. The increased number of infiltrated immune cells, the long survival time and the absence of side effects suggest that ICOCAV15 could be a safe and effective treatment and should be further explored as a novel therapy for canine hemangiomas.

Selective atrophy of the cervical enlargement in whole spinal cord MRI of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a deadly neurodegenerative disorder affecting motor neurons in the spinal cord and brain. Studies have reported on atrophy within segments of the cervical cord, but we are not aware of previous investigations of the whole spinal cord. Herein we present our findings from a 3T MRI study involving 32 subjects (15 ALS participants and 17 healthy controls) characterizing cross-sectional area along the entire cord. We report atrophy of the cervical enlargement in ALS participants, but no evidence of atrophy of the thoracolumbar enlargement. These results suggest that MR-based analyses of the cervical cord may be sufficient for in vivo investigations of spinal cord atrophy in ALS, and that atrophy of the cervical enlargement (C4-C7) is a potential imaging marker for quantifying lower motor neuron degradation.

Implementation of ISO/IEEE 11073 PHD SpO2 and ECG Device Specializations over Bluetooth HDP following Health Care Profile for Smart Living.

Current m-Health scenarios in the smart living era, as the interpretation of the smart city at each person's level, present several challenges associated with interoperability between different clinical devices and applications. The Continua Health Alliance establishes design guidelines to standardize application communication to guarantee interoperability among medical devices. In this paper, we describe the implementation of two IEEE agents for oxygen saturation level (SpO2) measurements and electrocardiogram (ECG) data acquisition, respectively, and a smartphone IEEE manager for validation. We developed both IEEE agents over the Bluetooth Health Device Profile following the Continua guidelines and they are part of a telemonitoring system. This system was evaluated in a sample composed of 10 volunteers (mean age 29.8 ± 7.1 y/o; 5 females) under supervision of an expert cardiologist. The evaluation consisted of measuring the SpO2 and ECG signal sitting and at rest, before and after exercising for 15 min. Physiological measurements were assessed and compared against commercial devices, and our expert physician did not find any relevant differences in the ECG signal. Additionally, the system was assessed when acquiring and processing different heart rate data to prove that warnings were generated when the heart rate was under/above the thresholds for bradycardia and tachycardia, respectively.

Multimodal Investigation of Neuroinflammation in Aviremic Patients With HIV on Antiretroviral Therapy and HIV Elite Controllers.

BACKGROUND AND OBJECTIVES: The presence of HIV in the CNS has been related to chronic immune activation and cognitive dysfunction. The aim of this work was to investigate (1) the presence of neuroinflammation in aviremic people with HIV (PWH) on therapy and in nontreated aviremic PWH (elite controllers [ECs]) using a translocator protein 18 kDa radioligand; (2) the relationship between neuroinflammation and cognitive function in aviremic PWH; and (3) the relationship between [11C]-PBR28 signal and quantitative MRI (qMRI) measures of brain tissue integrity such as T1 and T2 relaxation times (rts). METHODS: [11C]-PBR28 (standard uptake value ratio, SUVR) images were generated in 36 participants (14 PWH, 6 ECs, and 16 healthy controls) using a statistically defined pseudoreference region. Group comparisons of [11C]-PBR28 SUVR were performed using region of interest-based and voxelwise analyses. The relationship between inflammation, qMRI measures, and cognitive function was studied. RESULTS: In region of interest analyses, ECs exhibited significantly lower [11C]-PBR28 signal in the thalamus, putamen, superior temporal gyrus, prefrontal cortex, and cerebellum compared with the PWH. In voxelwise analyses, differences were observed in the thalamus, precuneus cortex, inferior temporal gyrus, occipital cortex, cerebellum, and white matter (WM). [11C]-PBR28 signal in the WM and superior temporal gyrus was related to processing speed and selective attention in PWH. In a subset of PWH (n = 12), [11C]-PBR28 signal in the thalamus and WM regions was related to a decrease in T2 rt and to an increase in T1 rt suggesting a colocalization of increased glial metabolism, decrease in microstructural integrity, and iron accumulation. DISCUSSION: This study casts a new light onto the role of neuroinflammation and related microstructural alterations of HIV infection in the CNS and shows that ECs suppress neuroinflammation more effectively than PWH on therapy.

Evaluation of Deep Learning-Based Approaches to Segment Bowel Air Pockets and Generate Pelvic Attenuation Maps from CAIPIRINHA-Accelerated Dixon MR Images.

Attenuation correction remains a challenge in pelvic PET/MRI. In addition to the segmentation/model-based approaches, deep learning methods have shown promise in synthesizing accurate pelvic attenuation maps (µ-maps). However, these methods often misclassify air pockets in the digestive tract, potentially introducing bias in the reconstructed PET images. The aims of this work were to develop deep learning-based methods to automatically segment air pockets and generate pseudo-CT images from CAIPIRINHA-accelerated MR Dixon images. Methods: A convolutional neural network (CNN) was trained to segment air pockets using 3-dimensional CAIPIRINHA-accelerated MR Dixon datasets from 35 subjects and was evaluated against semiautomated segmentations. A separate CNN was trained to synthesize pseudo-CT µ-maps from the Dixon images. Its accuracy was evaluated by comparing the deep learning-, model-, and CT-based µ-maps using data from 30 of the subjects. Finally, the impact of different µ-maps and air pocket segmentation methods on the PET quantification was investigated. Results: Air pockets segmented using the CNN agreed well with semiautomated segmentations, with a mean Dice similarity coefficient of 0.75. The volumetric similarity score between 2 segmentations was 0.85 ± 0.14. The mean absolute relative changes with respect to the CT-based µ-maps were 2.6% and 5.1% in the whole pelvis for the deep learning-based and model-based µ-maps, respectively. The average relative change between PET images reconstructed with deep learning-based and CT-based µ-maps was 2.6%. Conclusion: We developed a deep learning-based method to automatically segment air pockets from CAIPIRINHA-accelerated Dixon images, with accuracy comparable to that of semiautomatic segmentations. The µ-maps synthesized using a deep learning-based method from CAIPIRINHA-accelerated Dixon images were more accurate than those generated with the model-based approach available on integrated PET/MRI scanners.

PET/MRI and PET/CT Radiomics in Primary Cervical Cancer: A Pilot Study on the Correlation of Pelvic PET, MRI, and CT Derived Image Features.

PURPOSE: To evaluate the correlation of radiomic features in pelvic [2-deoxy-2-18F]fluoro-D-glucose positron emission tomography/magnetic resonance imaging and computed tomography ([18F]FDG PET/MRI and [18F]FDG PET/CT) in patients with primary cervical cancer (CCa). PROCEDURES: Nineteen patients with histologically confirmed primary squamous cell carcinoma of the cervix underwent same-day [18F]FDG PET/MRI and PET/CT. Two nuclear medicine physicians performed a consensus reading in random order. Free-hand regions of interest covering the primary cervical tumors were drawn on PET, contrast-enhanced pelvic CT, and pelvic MR (T2 weighted and ADC) images. Several basic imaging features, standard uptake values (SUVmean, SUVmax, and SUVpeak), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and more advanced texture analysis features were calculated. Pearson's correlation test was used to assess the correlation between each pair of features. Features were compared between local and metastatic tumors, and their role in predicting metastasis was evaluated by receiver operating characteristic curves. RESULTS: For a total of 101 extracted features, 1104/5050 pairs of features showed a significant correlation (ρ ≥ 0.70, p < 0.05). There was a strong correlation between 190/484 PET pairs of features from PET/MRI and PET/CT, 91/418 pairs of CT and PET from PET/CT, 79/418 pairs of T2 and PET from PET/MRI, and 50/418 pairs of ADC and PET from PET/MRI. Significant difference was seen between eight features in local and metastatic tumors including MTV, TLG, and entropy on PET from PET/CT; MTV and TLG on PET from PET/MRI; compactness and entropy on T2; and entropy on ADC images. CONCLUSIONS: We demonstrated strong correlation of many extracted radiomic features between PET/MRI and PET/CT. Eight radiomic features calculated on PET/CT and PET/MRI were significantly different between local and metastatic CCa. This study paves the way for future studies to evaluate the diagnostic and predictive potential of radiomics that could guide clinicians toward personalized patients care.

Neuroimmune signatures in chronic low back pain subtypes.

We recently showed that patients with different chronic pain conditions (such as chronic low back pain, fibromyalgia, migraine and Gulf War illness) demonstrated elevated brain and/or spinal cord levels of the glial marker 18-kDa translocator protein (TSPO), which suggests that neuroinflammation might be a pervasive phenomenon observable across multiple aetiologically heterogeneous pain disorders. Interestingly, the spatial distribution of this neuroinflammatory signal appears to exhibit a degree of disease specificity (e.g. with respect to the involvement of the primary somatosensory cortex), suggesting that different pain conditions may exhibit distinct 'neuroinflammatory signatures'. To explore this hypothesis further, we tested whether neuroinflammatory signal can characterize putative aetiological subtypes of chronic low back pain patients based on clinical presentation. Specifically, we explored neuroinflammation in patients whose chronic low back pain either did or did not radiate to the leg (i.e. 'radicular' versus 'axial' back pain). Fifty-four patients with chronic low back pain, 26 with axial back pain [43.7 ± 16.6 years old (mean ± SD)] and 28 with radicular back pain (48.3 ± 13.2 years old), underwent PET/MRI with 11C-PBR28, a second-generation radioligand for TSPO. 11C-PBR28 signal was quantified using standardized uptake values ratio (validated against volume of distribution ratio; n = 23). Functional MRI data were collected simultaneously to the 11C-PBR28 data (i) to functionally localize the primary somatosensory cortex back and leg subregions; and (ii) to perform functional connectivity analyses (in order to investigate possible neurophysiological correlations of the neuroinflammatory signal). PET and functional MRI measures were compared across groups, cross-correlated with one another and with the severity of 'fibromyalgianess' (i.e. the degree of pain centralization, or 'nociplastic pain'). Furthermore, statistical mediation models were used to explore possible causal relationships between these three variables. For the primary somatosensory cortex representation of back/leg, 11C-PBR28 PET signal and functional connectivity to the thalamus were: (i) higher in radicular compared to axial back pain patients; (ii) positively correlated with each other; (iii) positively correlated with fibromyalgianess scores, across groups; and finally (iv) fibromyalgianess mediated the association between 11C-PBR28 PET signal and primary somatosensory cortex-thalamus connectivity across groups. Our findings support the existence of 'neuroinflammatory signatures' that are accompanied by neurophysiological changes and correlate with clinical presentation (in particular, with the degree of nociplastic pain) in chronic pain patients. These signatures may contribute to the subtyping of distinct pain syndromes and also provide information about interindividual variability in neuroimmune brain signals, within diagnostic groups, that could eventually serve as targets for mechanism-based precision medicine approaches.

[11C]PBR28 radiotracer kinetics are not driven by alterations in cerebral blood flow.

The positron emission tomography (PET) radiotracer [11C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [11C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [11C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [11C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [11C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [11C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.

3D magnetic resonance spectroscopic imaging reveals links between brain metabolites and multidimensional pain features in fibromyalgia.

BACKGROUND: Fibromyalgia is a centralized multidimensional chronic pain syndrome, but its pathophysiology is not fully understood. METHODS: We applied 3D magnetic resonance spectroscopic imaging (MRSI), covering multiple cortical and subcortical brain regions, to investigate the association between neuro-metabolite (e.g. combined glutamate and glutamine, Glx; myo-inositol, mIno; and combined (total) N-acetylaspartate and N-acetylaspartylglutamate, tNAA) levels and multidimensional clinical/behavioural variables (e.g. pain catastrophizing, clinical pain severity and evoked pain sensitivity) in women with fibromyalgia (N = 87). RESULTS: Pain catastrophizing scores were positively correlated with Glx and tNAA levels in insular cortex, and negatively correlated with mIno levels in posterior cingulate cortex (PCC). Clinical pain severity was positively correlated with Glx levels in insula and PCC, and with tNAA levels in anterior midcingulate cortex (aMCC), but negatively correlated with mIno levels in aMCC and thalamus. Evoked pain sensitivity was negatively correlated with levels of tNAA in insular cortex, MCC, PCC and thalamus. CONCLUSIONS: These findings support single voxel placement targeting nociceptive processing areas in prior 1 H-MRS studies, but also highlight other areas not as commonly targeted, such as PCC, as important for chronic pain pathophysiology. Identifying target brain regions linked to multidimensional symptoms of fibromyalgia (e.g. negative cognitive/affective response to pain, clinical pain, evoked pain sensitivity) may aid the development of neuromodulatory and individualized therapies. Furthermore, efficient multi-region sampling with 3D MRSI could reduce the burden of lengthy scan time for clinical research applications of molecular brain-based mechanisms supporting multidimensional aspects of fibromyalgia. SIGNIFICANCE: This large N study linked brain metabolites and pain features in fibromyalgia patients, with a better spatial resolution and brain coverage, to understand a molecular mechanism underlying pain catastrophizing and other aspects of pain transmission. Metabolite levels in self-referential cognitive processing area as well as pain-processing regions were associated with pain outcomes. These results could help the understanding of its pathophysiology and treatment strategies for clinicians.

An international expert opinion statement on the utility of PET/MR for imaging of skeletal metastases.

BACKGROUND: MR is an important imaging modality for evaluating musculoskeletal malignancies owing to its high soft tissue contrast and its ability to acquire multiparametric information. PET provides quantitative molecular and physiologic information and is a critical tool in the diagnosis and staging of several malignancies. PET/MR, which can take advantage of its constituent modalities, is uniquely suited for evaluating skeletal metastases. We reviewed the current evidence of PET/MR in assessing for skeletal metastases and provided recommendations for its use. METHODS: We searched for the peer reviewed literature related to the usage of PET/MR in the settings of osseous metastases. In addition, expert opinions, practices, and protocols of major research institutions performing research on PET/MR of skeletal metastases were considered. RESULTS: Peer-reviewed published literature was included. Nuclear medicine and radiology experts, including those from 13 major PET/MR centers, shared the gained expertise on PET/MR use for evaluating skeletal metastases and contributed to a consensus expert opinion statement. [18F]-FDG and non [18F]-FDG PET/MR may provide key advantages over PET/CT in the evaluation for osseous metastases in several primary malignancies. CONCLUSION: PET/MR should be considered for staging of malignancies where there is a high likelihood of osseous metastatic disease based on the characteristics of the primary malignancy, hight clinical suspicious and in case, where the presence of osseous metastases will have an impact on patient management. Appropriate choice of tumor-specific radiopharmaceuticals, as well as stringent adherence to PET and MR protocols, should be employed.

Thalamic neurometabolite alterations in patients with knee osteoarthritis before and after total knee replacement.

ABSTRACT: The weak association between disability levels and "peripheral" (ie, knee) findings suggests that central nervous system alterations may contribute to the pathophysiology of knee osteoarthritis (KOA). Here, we evaluated brain metabolite alterations in patients with KOA, before and after total knee arthroplasty (TKA), using 1H-magnetic resonance spectroscopy (MRS). Thirty-four presurgical patients with KOA and 13 healthy controls were scanned using a PRESS sequence (TE = 30 ms, TR = 1.7 seconds, voxel size = 15 × 15 × 15 mm). In addition, 13 patients were rescanned 4.1 ± 1.6 (mean ± SD) weeks post-TKA. When using creatine (Cr)-normalized levels, presurgical KOA patients demonstrated lower N-acetylaspartate (NAA) (P < 0.001), higher myoinositol (mIns) (P < 0.001), and lower Choline (Cho) (P < 0.05) than healthy controls. The mIns levels were positively correlated with pain severity scores (r = 0.37, P < 0.05). These effects reached statistical significance also using water-referenced concentrations, except for the Cho group differences (P ≥ 0.067). Post-TKA patients demonstrated an increase in NAA (P < 0.01), which returned to the levels of healthy controls (P > 0.05), irrespective of metric. In addition, patients demonstrated postsurgical increases in Cr-normalized (P < 0.001), but not water-referenced mIns, which were proportional to the NAA/Cr increases (r = 0.61, P < 0.05). Because mIns is commonly regarded as a glial marker, our results are suggestive of a possible dual role for neuroinflammation in KOA pain and post-TKA recovery. Moreover, the apparent postsurgical normalization of NAA, a putative marker of neuronal integrity, might implicate mitochondrial dysfunction, rather than neurodegenerative processes, as a plausible pathophysiological mechanism in KOA. More broadly, our results add to a growing body of literature suggesting that some pain-related brain alterations can be reversed after peripheral surgical treatment.