Physiological Imaging Techniques Research Articles

Assessing Mild Traumatic Brain Injury-Associated Blood–Brain Barrier (BBB) Damage and Restoration Using Late-Phase Perfusion Analysis by 3D ASL MRI: Implications for Predicting Progressive Brain Injury in a Focused Review

Mild traumatic brain injury (mTBI) is a common occurrence around the world, associated with a variety of blunt force and torsion injuries affecting all age groups. Most never reach medical attention, and the identification of acute injury and later clearance to return to usual activities is relegated to clinical evaluation—particularly in sports injuries. Advanced structural imaging is rarely performed due to the usual absence of associated acute anatomic/hemorrhagic changes. This review targets physiologic imaging techniques available to identify subtle blood–brain barrier dysfunction and white matter tract shear injury and their association with chronic traumatic encephalopathy. These techniques provide needed objective measures to assure recovery from injury in those patients with persistent cognitive/emotional symptoms and in the face of repetitive mTBI.

Identifying sex differences in EEG-based emotion recognition using graph convolutional network with attention mechanism

Objective. Sex differences in emotions have been widely perceived via self-reports, peripheral physiological signals and brain imaging techniques. However, how sex differences are reflected in the electroencephalography (EEG) neural patterns of emotions remains unresolved. In this paper, we detect sex differences in emotional EEG patterns, investigate the consistency of such differences in various emotion datasets across cultures, and study how sex as a factor affects the performance of EEG-based emotion recognition models. Approach. We thoroughly assess sex differences in emotional EEG patterns on five public datasets, including SEED, SEED-IV, SEED-V, DEAP and DREAMER, systematically examine the sex-specific EEG patterns for happy, sad, fearful, disgusted and neutral emotions, and implement deep learning models for sex-specific emotion recognition. Main results. (1) Sex differences exist in various emotion types and both Western and Eastern cultures; (2) The emotion patterns of females are more stable than those of males, and the patterns of happiness from females are in sharp contrast with the patterns of sadness, fear and disgust, while the energy levels are more balanced for males; (3) The key features for emotion recognition are mainly located at the frontal and temporal sites for females and distributed more evenly over the whole brain for males, and (4) the same-sex emotion recognition models outperform the corresponding cross-sex models. Significance. These findings extend efforts to characterize sex differences in emotional brain activation, provide new physiological evidence for sex-specific emotion processing, and reinforce the message that sex differences should be carefully considered in affective research and precision medicine.

Evaluating Physiological MRI Parameters in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery-A Preliminary Analysis and Case Report.

Brain metastases occur in ten to thirty percent of the adult cancer population. Treatment consists of different (palliative) options, including stereotactic radiosurgery (SRS). Sensitive MRI biomarkers are needed to better understand radiotherapy-related effects on cerebral physiology and the subsequent effects on neurocognitive functioning. In the current study, we used physiological imaging techniques to assess cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2) and cerebrovascular reactivity (CVR) before and three months after SRS in nine patients with brain metastases. The results showed improvement in OEF, CBF and CMRO2 within brain tissue that recovered from edema (all p ≤ 0.04), while CVR remained impacted. We observed a global post-radiotherapy increase in CBF in healthy-appearing brain tissue (p = 0.02). A repeated measures correlation analysis showed larger reductions within regions exposed to higher radiotherapy doses in CBF (rrm = -0.286, p < 0.001), CMRO2 (rrm = -0.254, p < 0.001), and CVR (rrm = -0.346, p < 0.001), but not in OEF (rrm = -0.004, p = 0.954). Case analyses illustrated the impact of brain metastases progression on the post-radiotherapy changes in both physiological MRI measures and cognitive performance. Our preliminary findings suggest no radiotherapy effects on physiological parameters occurred in healthy-appearing brain tissue within 3-months post-radiotherapy. Nevertheless, as radiotherapy can have late side effects, larger patient samples allowing meaningful grouping of patients and longer follow-ups are needed.

Leaf mesophyll K+ and Cl− fluxes and reactive oxygen species production predict rice salt tolerance at reproductive stage in greenhouse and field conditions

Extensive research on salinity tolerance in rice has been mostly carried out at the seedling stage in single experimental trials. Here, we aimed to understand the roles of ion transport and oxidative responses of leaf mesophyll in salinity tolerance of rice (Oryza sativa L.) at its reproductive stage using comparative investigations in both greenhouse and field trials. Two experimental trials were conducted to assess the salt tolerance of three rice cultivars at their reproductive stage in greenhouse and field. We employed agronomic, physiological, electrophysiological, molecular and cell imaging techniques to compare physiological response of control and salinity stressed rice plants. Salinity had the most severe effect to Koshihikari, followed by Doongara and Reiziq. We found that K+ retention and low recovery Cl− efflux in mesophyll cells confers salt tolerance in rice. Moderate to strong correlations were found between growth parameters and net K+ flux (r2 = 0.45–0.60), and net Cl− flux (r2 = 0.47–0.72). Also, dynamic ROS production and regulation of the NADPH oxidase gene, OsRBOHD, in mesophyll cells is crucial for salt tolerance of rice at the reproductive stage. OsRBOHD expression was significantly correlated to recovery ion fluxes (r2 = 0.45–0.64). This study brings together, for the first time, potential links between cellular ionic stress and oxidative stress components of salinity tolerance in rice at the reproductive stage in both greenhouse and field conditions. Our study will provide guidance to examine crop salinity tolerance at reproductive stages in controlled environments and natural climatic conditions in the future.

Morphological and physiological responses of the potato stem transport tissues to dehydration stress

Main conclusionAdaptation of the xylem under dehydration to smaller sized vessels and the increase in xylem density per stem area facilitate water transport during water-limiting conditions, and this has implications for assimilate transport during drought.The potato stem is the communication and transport channel between the assimilate-exporting source leaves and the terminal sink tissues of the plant. During environmental stress conditions like water scarcity, which adversely affect the performance (canopy growth and tuber yield) of the potato plant, the response of stem tissues is essential, however, still understudied. In this study, we investigated the response of the stem tissues of cultivated potato grown in the greenhouse to dehydration using a multidisciplinary approach including physiological, biochemical, morphological, microscopic, and magnetic resonance imaging techniques. We observed the most significant effects of water limitation in the lower stem regions of plants. The light microscopy analysis of the potato stem sections revealed that plants exposed to this particular dehydration stress have higher total xylem density per unit area than control plants. This increase in the total xylem density was accompanied by an increase in the number of narrow-diameter xylem vessels and a decrease in the number of large-diameter xylem vessels. Our MRI approach revealed a diurnal rhythm of xylem flux between day and night, with a reduction in xylem flux that is linked to dehydration sensitivity. We also observed that sink strength was the main driver of assimilate transport through the stem in our data set. These findings may present potential breeding targets for drought tolerance in potato.

Chapter 12 - Modern day imaging of meningiomas

Meningiomas are the most common primary tumors of the central nervous system and as such they are often encountered at neuroimaging. Fortunately, meningiomas are readily diagnosed with anatomic computed tomography and magnetic resonance imaging. While conventional imaging is the mainstay for initial diagnosis and delineating tumor for treatment planning and posttreatment follow-up, the last couple of decades have given rise to advanced physiologic and metabolic imaging techniques that serve as powerful tools in the management of meningioma. These modern approaches are allowing imaging to expand its utility to include extraction of biologic and potentially prognostic information that will ultimately improve care for meningioma patients.

Researches on empathy: Methodologies and characteristics from a psychophysiological perspective

Empathy is an essential skill in our social lives, allowing us to understand and share others’ feelings. In the last decade, empathy has been a hot topic in cognitive neuroscience for its important role in social interaction. To date, there are a variety of definitions of the term “empathy”, such as “a reaction to the observed experiences of another” and “the ability to experience and understand what others feel without confusion between oneself and others”. Based on different definitions of empathy, different methodologies have been developed and adopted in the field of empathy research. Valid empathy questionnaires are developed to provide ones’ subjective evaluation about their empathy ability (i.e., trait empathy); behavioral paradigms are designed to measure individuals’ empathy levels under a specific context (i.e., state empathy); physiological techniques and brain imaging techniques are useful in detecting objective physiological signals related to empathy. However, some findings on empathy are mixed and inconsistent, which might be due to the different definitions and methodologies adopted by each study. To deepen our understanding of empathy and its psychological mechanisms, it is necessary to integrate different methodologies and interpret results from different aspects. To this end, this review first summarized how empathy is typically measured and quantified at different measurement levels with an emphasis on emotional empathy and cognitive empathy, given that existing studies on empathy mainly focus on the two categories and their combination. Specifically, methodologies in empathy research were introduced as followed: (1) Widely-used empathy questionnaires, including the detailed definitions and measurement dimensions; (2) classic experimental materials and behavioral paradigms for measuring emotional empathy and/or cognitive empathy; (3) empathy-related physiological signals detected by facial electromyography, electroencephalography (EEG), magnetoencephalography (MEG), and magnetic resonance imaging (MRI). Next, we discussed the advantages and disadvantages of each methodology and pointed out the difficulties in compiling findings from studies using different methodologies. For example, different empathy questionnaires applied to the same group may yield contradictory results and the quality of experimental stimulus in the same kind of empathy paradigms potentially influences participants’ brain activities. More importantly, the physiological signals (e.g. event-related potential components) recorded in empathy experiments are not “specific” but only “related” to empathy. Then, we suggested that researchers should carefully select appropriate methodologies according to their research needs. For instance, EEG is suitable for exploring empathic processing in the time domain, while functional magnetic resonance imaging (fMRI) is conducive to pinpoint the specific functions (e.g. self-other discrimination) of empathy-related brain regions. Finally, we proposed that the conceptual framework of empathy should be unified and more naturalistic paradigms should be developed to reveal the interactions among different empathic subprocesses in the future. In conclusion, this review highlights the importance of comparing and combining different methodologies in order to reveal the underlying mechanisms of empathy, which yields new insights into social interaction.

A Mathematical Model for the Sounds Produced by Knuckle Cracking

The articular release of the metacarpophalangeal joint produces a typical cracking sound, resulting in what is commonly referred to as the cracking of knuckles. Despite over sixty years of research, the source of the knuckle cracking sound continues to be debated due to inconclusive experimental evidence as a result of limitations in the temporal resolution of non-invasive physiological imaging techniques. To support the available experimental data and shed light onto the source of the cracking sound, we have developed a mathematical model of the events leading to the generation of the sound. The model resolves the dynamics of a collapsing cavitation bubble in the synovial fluid inside a metacarpophalangeal joint during an articular release. The acoustic signature from the resulting bubble dynamics is shown to be consistent in both magnitude and dominant frequency with experimental measurements in the literature and with our own experiments, thus lending support for cavitation bubble collapse as the source of the cracking sound. Finally, the model also shows that only a partial collapse of the bubble is needed to replicate the experimentally observed acoustic spectra, thus allowing for bubbles to persist following the generation of sound as has been reported in recent experiments.

Current evidence for endovascular therapy in stroke and remaining uncertainties.

Class 1 level A evidence now supports endovascular thrombectomy as best practice in the management of large vessel occlusion acute ischaemic stroke. However, significant questions pertaining to initial imaging, radiological assessment, patient selection and therapeutic limits remain unanswered. A specific cohort of patients who benefit from endovascular thrombectomy has been established, although current uncertainties regarding selection of those not meeting top-tier evidence criteria may potentially deny certain patients the benefit of intervention. This is of particular relevance in patients presenting in a delayed manner. Whilst superior outcomes are achieved with reduced time to endovascular reperfusion, denying patients intervention based on symptom duration alone may not be appropriate. Advanced understanding of ischaemic stroke pathophysiology supports an individualized approach to patient evaluation, given variance in the rate of ischaemic core progression and the extent of salvageable penumbra. Physiological imaging techniques may therefore be utilized to better inform patient selection for endovascular thrombectomy and evidence suggests that a transition from time-based to tissue-based therapeutic thresholds may be of greater value. Multiple ongoing randomized controlled trials aim to further define the benefit of endovascular thrombectomy and it is hoped that these results will advance, and possibly broaden, patient selection criteria to ensure that maximum benefit from the intervention may be achieved.

Advances in pediatric epilepsy neuroimaging

Epilepsy is a chronic brain disorder defined by recurrent seizures. Onset may occur early in life, and in fact most often occurs in childhood. The diagnosis and management of childhood epilepsy is more challenging than in adults, in part because of the rich diversity of underlying etiologies ranging from early cerebral anoxia, infection, metabolic disorders, developmental brain malformations, to those also found in young adulthood including hippocampal sclerosis, vascular malformations, primary brain neoplasms, and traumatic brain injury. Neuroimaging plays an important role in identifying the specific underlying pathology and in guiding treatment, and also provides information necessary for etiologic diagnosis, such as in various epilepsy syndromes, and hence prognosis for the affected child and family. Magnetic resonance imaging (MRI) is themost important noninvasive imaging modality, and is mandated in the pre-surgical evaluation of children with epilepsy together with electroencephalography (EEG). Several series have documented that complete lesional resection is the best predictor for favorable postsurgical outcomes. While structural MRI provides exquisite anatomic delineation because of its high spatial resolution and intrinsic soft tissue contrast, it also has its limitations. For instance, MRI may fail to identify subtle lesions that account for up to 20–30% of refractory partial epilepsy, often related to subtle focal cortical dysplasia with microdysgenesis only revealed on histopathology. The identification of these lesions may be possible with other imaging modalities such as positron emission tomography (PET) or, in some instances, diffusion tensor imaging. In addition, in multifocal or diffuse diseases (such as in tuberous sclerosis), even though structural abnormalities can be sensitively depicted by MRI, it may be difficult to determine which of the lesions are epileptogenic and therefore targeted for surgical intervention. In such cases, additional information afforded by advanced MRI or physiologic imaging techniques including diffusion weighted imaging (DWI), MR spectroscopy, and single photon emission computed tomography (SPECT) or PET may be useful. Pre-surgical localization of these lesions, surgical planning and predicting outcome is therefore best accomplished by a multi-modality approach, incorporating structural, functional and physiologic techniques (including functional MRI [fMRI], and magnetoencephalography [MEG]) in addition to the EEG. To date, many of the advanced physiological and functional imaging modalities have not been extensively validated in the evaluation of childhood epilepsy, and they therefore are not part of routine pre-surgical evaluation of such patients in many institutions. They do, however, hold immense promise. For example, incorporation of fMRI may allow refinement of surgical resection *Corresponding author: Doris D.M. Lin, MD, PhD, Division of Neuroradiology, Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Phipps B-100, Baltimore, MD 21287, USA. Tel.: +1 443 287 3079; Fax: +1 410 614 1213; E-mail: ddmlin@JHMI.edu. Journal of Pediatric Epilepsy 2 (2013) 1–2 DOI 10.3233/PEP-13045 IOS Press 1

Physiologic imaging in acute stroke: Patient selection.

Treatment of acute stroke is changing, as endovascular intervention becomes an important adjunct to tissue plasminogen activator. An increasing number of sophisticated physiologic imaging techniques have unique advantages and applications in the evaluation, diagnosis, and treatment-decision making of acute ischemic stroke. In this review, we first highlight the strengths, weaknesses, and possible indications for various stroke imaging techniques. How acute imaging findings in each modality have been used to predict functional outcome is discussed. Furthermore, there is an increasing emphasis on using these state-of-the-art imaging modalities to offer maximal patient benefit through IV therapy, endovascular thrombolytics, and clot retrieval. We review the burgeoning literature in the determination of stroke treatment based on acute, physiologic imaging findings.

Response Assessment and Magnetic Resonance Imaging Issues for Clinical Trials Involving High-Grade Gliomas.

There exist multiple challenges associated with the current response assessment criteria for high-grade gliomas, including the uncertain role of changes in nonenhancing T2 hyperintensity, and the phenomena of pseudoresponse and pseudoprogression in the setting of antiangiogenic and chemoradiation therapies, respectively. Advanced physiological magnetic resonance imaging (MRI), including diffusion and perfusion (dynamic susceptibility contrast MRI and dynamic contrast-enhanced MRI) sensitive techniques for overcoming response assessment challenges, has been proposed, with their own potential advantages and inherent shortcomings. Measurement variability exists for conventional and advanced MRI techniques, necessitating the standardization of image acquisition parameters in order to establish the utility of these imaging methods in multicenter trials for high-grade gliomas. This review chapter highlights the important features of MRI in clinical brain tumor trials, focusing on the current state of response assessment in brain tumors, advanced imaging techniques that may provide additional value for determining response, and imaging issues to be considered for multicenter trials.

Chronic cerebrospinal venous insufficiency: pitfalls and perils of sonographic assessment.

Duplex sonography has been proposed as a diagnostic modality for detection of chronic cerebrovascular venous insufficiency, a recently proposed hypothesis of multiple sclerosis (MS) pathogenesis. We reviewed potential challenges of duplex sonography for diagnosis of chronic cerebrovascular venous insufficiency and used interim pooled data from a study aimed to apply cerebrovascular venous insufficiency criteria to a group of patients with MS and control patients without MS. Duplex sonography for chronic cerebrovascular venous insufficiency was performed in patients with MS and controls. Extracranial and deep cerebral veins were studied by using a published chronic cerebrovascular venous insufficiency protocol and criteria. Comparative imaging was performed to explore how physiologic factors and imaging techniques could affect key parameters. The effects of varying definitions on fulfilling chronic cerebrovascular venous insufficiency diagnostic criteria were also explored. Forty-two patients were enrolled. Twenty-five (60%) had a reduction in internal jugular vein cross-sectional area by 50% or more, cross-sectional area of 0.3 cm(2) or less, and/or a B-mode abnormality. No patients had reflux longer than 0.88 seconds in both sitting and supine positions, the presence of duplex sonographic reflux on transcranial Doppler imaging, or a larger internal jugular vein cross-sectional area in the sitting versus supine position. Fourteen patients (33.3%) had either a flap or septum, and 1 had a web. Collateral veins to the vertebral veins were identified in 14 of 42 patients (33.3%). The use of transcranial Doppler imaging versus quality Doppler profiles resulted in fewer patients meeting criteria for chronic cerebrovascular venous insufficiency. There are several important variables, including physiologic, technical, and criterion definitions, in the application of sonographic assessment of chronic cerebrovascular venous insufficiency that may affect diagnostic accuracy.

Rise of Functional Neuroradiologists in Clinical Care

Recent translational advances in neuroimaging herald a fundamental shift in the practice of Neuroradiology. Biological, physiological, microstructural, metabolic, and functional imaging techniques have bridged the gaps between clinical imaging and the clinical neurosciences. These advancements are guiding the transition of neuroradiology from traditional pattern-based, image-centric toward knowledge-based, patient-centric practice strategies. The willingness of the neuroradiologist to embrace this shift is critical to the process. The chapter highlights the expanding role and importance of the functional neuroradiologist in clinical care.

Recruitment maneuvers in acute respiratory distress syndrome: The safe way is the best way.

Acute respiratory distress syndrome (ARDS) represents a serious problem in critically ill patients and is associated with in-hospital mortality rates of 33%-52%. Recruitment maneuvers (RMs) are a simple, low-cost, feasible intervention that can be performed at the bedside in patients with ARDS. RMs are characterized by the application of airway pressure to increase transpulmonary pressure transiently. Once non-aerated lung units are reopened, improvements are observed in respiratory system mechanics, alveolar reaeration on computed tomography, and improvements in gas exchange (functional recruitment). However, the reopening process could lead to vascular compression, which can be associated with overinflation, and gas exchange may not improve as expected (anatomical recruitment). The purpose of this review was to discuss the effects of different RM strategies - sustained inflation, intermittent sighs, and stepwise increases of positive end-expiratory pressure (PEEP) and/or airway inspiratory pressure - on the following parameters: hemodynamics, oxygenation, barotrauma episodes, and lung recruitability through physiological variables and imaging techniques. RMs and PEEP titration are interdependent events for the success of ventilatory management. PEEP should be adjusted on the basis of respiratory system mechanics and oxygenation. Recent systematic reviews and meta-analyses suggest that RMs are associated with lower mortality in patients with ARDS. However, the optimal RM method (i.e., that providing the best balance of benefit and harm) and the effects of RMs on clinical outcome are still under discussion, and further evidence is needed.

Biology, genetics and imaging of glial cell tumours

Despite advances in therapy, gliomas remain associated with poor prognosis. Clinical advances will be achieved through molecularly targeted biological therapies, for which knowledge of molecular genetic and gene expression characteristics in relation to histopathology and in vivo imaging are essential. Recent research supports the molecular classification of gliomas based on genetic alterations or gene expression profiles, and imaging data supports the concept that molecular subtypes of glioma may be distinguished through non-invasive anatomical, physiological and metabolic imaging techniques, suggesting differences in the baseline biology of genetic subtypes of infiltrating glioma. Furthermore, MRI signatures are now being associated with complex gene expression profiles and cellular signalling pathways through genome-wide microarray studies using samples obtained by image guidance which may be co-registered with clinical imaging. In this review we describe the pathobiology, molecular pathogenesis, stem cells and imaging characteristics of gliomas with emphasis on astrocytomas and oligodendroglial neoplasms.

Advanced MRI of articular cartilage

Musculoskeletal MRI is advancing rapidly, with innovative technology and significant potential for immediate clinical impact. In particular, cartilage imaging has become a topic of increasing interest as our aging population develops diseases such as osteoarthritis. Advances in MRI hardware and software have led to increased image quality and tissue contrast. Additional developments have allowed the assessment of cartilage macromolecular content, which may be crucial to the early detection of musculoskeletal diseases. This comprehensive article considers current morphological and physiological cartilage imaging techniques, their clinical applications, and their potential to contribute to future improvements in the imaging of cartilage.

A novel planar tracking technology for physiological image analysis

Automated image tracking provides new insights in many physiological studies, but present methods are ad hoc and can be difficult to use. They are generally based on following the movement of one or more specific regions of interested - point tracking. We tested newly available novel planar tracking technology commercially developed for the special effects industry, which does not use point tracking. We validated the tracker and made two dynamic physiological measurements. Our validation measurements describe the accuracy and repeatability of the technique, and our physiological measurements demonstrate the flexibility of the software. Our results suggest that planar tracking may be of particular use with techniques that produce low quality images such as ultrasonography.

Advancements in MR Imaging of the Prostate: From Diagnosis to Interventions

Prostate cancer is the most frequently diagnosed cancer in males and the second leading cause of cancer-related death in men. Assessment of prostate cancer can be divided into detection, localization, and staging; accurate assessment is a prerequisite for optimal clinical management and therapy selection. Magnetic resonance (MR) imaging has been shown to be of particular help in localization and staging of prostate cancer. Traditional prostate MR imaging has been based on morphologic imaging with standard T1-weighted and T2-weighted sequences, which has limited accuracy. Recent advances include additional functional and physiologic MR imaging techniques (diffusion-weighted imaging, MR spectroscopy, and perfusion imaging), which allow extension of the obtainable information beyond anatomic assessment. Multiparametric MR imaging provides the highest accuracy in diagnosis and staging of prostate cancer. In addition, improvements in MR imaging hardware and software (3-T vs 1.5-T imaging) continue to improve spatial and temporal resolution and the signal-to-noise ratio of MR imaging examinations. Another recent advancement in the field is MR imaging guidance for targeted prostate biopsy, which is an alternative to the current standard of transrectal ultrasonography-guided systematic biopsy.

Assessment of therapeutic response and treatment planning for brain tumors using metabolic and physiological MRI.

MRI is routinely used for diagnosis, treatment planning and assessment of response to therapy for patients with glioma. Gliomas are spatially heterogeneous and infiltrative lesions that are quite variable in terms of their response to therapy. Patients classified as having low-grade histology have a median overall survival of 7 years or more, but need to be monitored carefully to make sure that their tumor does not upgrade to a more malignant phenotype. Patients with the most aggressive grade IV histology have a median overall survival of 12-15 months and often undergo multiple surgeries and adjuvant therapies in an attempt to control their disease. Despite improvements in the spatial resolution and sensitivity of anatomic images, there remain considerable ambiguities in the interpretation of changes in the size of the gadolinium-enhancing lesion on T(1) -weighted images as a measure of treatment response, and in differentiating between treatment effects and infiltrating tumor within the larger T(2) lesion. The planning of focal therapies, such as surgery, radiation and targeted drug delivery, as well as a more reliable assessment of the response to therapy, would benefit considerably from the integration of metabolic and physiological imaging techniques into routine clinical MR examinations. Advanced methods that have been shown to provide valuable data for patients with glioma are diffusion, perfusion and spectroscopic imaging. Multiparametric examinations that include the acquisition of such data are able to assess tumor cellularity, hypoxia, disruption of normal tissue architecture, changes in vascular density and vessel permeability, in addition to the standard measures of changes in the volume of enhancing and nonenhancing anatomic lesions. This is particularly critical for the interpretation of the results of Phase I and Phase II clinical trials of novel therapies, which are increasingly including agents that are designed to have anti-angiogenic and anti-proliferative properties as opposed to having a direct effect on tumor cell viability.