Automated longitudinal registration of high resolution structural MRI brain sub-volumes in non-human primates

Accurate anatomic co-registration is a prerequisite for identifying structural and functional changes in longitudinal studies of brain plasticity. Current MRI methods permit collection of brain images across multiple scales, ranging from whole brain at relatively low resolution (≥1 mm), to local brain areas at the level of cortical layers and columns (∼100 μm) in the same session, allowing detection of subtle structural changes on a similar spatial scale. To measure these changes reliably, high resolution structural and functional images of local brain regions must be registered accurately across imaging sessions. The present study describes a robust fully automated strategy for the registration of high resolution structural images of brain sub-volumes to lower resolution whole brain images collected within a session, and the registration of partially overlapping high resolution MRI sub-volumes (“slabs”) across imaging sessions. In high field (9.4 T) reduced field-of-view high resolution structural imaging studies using a surface coil in an anesthetized non-human primate model, this fully automated coregistration pipeline was robust in the face of significant inhomogeneities in image intensity and tissue contrast arising from the spatially inhomogeneous transmit and receive properties of the surface coil, achieving a registration accuracy of 30 ± 15 μm between sessions.     

Magnetic resonance imaging,microscopy, and spectroscopy of the central nervous system in experimental animals

Over the last two decades, microscopic resolutionin vivo magnetic resonance imaging (MRI) techniques have been developed and extensively used in the study of animal models of human diseases. Standard MRI methods are frequently used in clinical studies and in the general clinical practice of human neurological diseases. This generates a need for similar studies in experimental animal research. Because small rodents are the most commonly used species as animal models of neurological diseases, the MRI techniques need to be able to provide microscopic resolution and high signal-to-noise ratio images in relatively short time. Small animal MRI systems use very high field-strength magnets, which results in higher signal to noise ratio; however, the contrast characteristics of live tissue are different at these field strengths. In addition to standard MRI techniques, several new applications have been implemented in experimental animals, including diffusion and perfusion studies, MR angiography, functional MRI studies, MRI tractography, proton and phosphorous spectroscopy, cellular and molecular imaging using novel contrast methods. Here we give an overview of how to establish a small animal imaging facility with the goal of CNS imaging. We describe the basic physical processes leading to MR signal generation, highlighting the differences between standard clinical MRI and small animal MRI. Finally, typical findings in the most common neurological disease categories and novel MRI/magnetic resonance spectroscopy methods used in their study are also described.     

MRI in Rodent Models of Brain Disorders

Magnetic resonance imaging (MRI) is a well-established tool in clinical practice and research on human neurological disorders. Translational MRI research utilizing rodent models of central nervous system (CNS) diseases is becoming popular with the increased availability of dedicated small animal MRI systems. Projects utilizing this technology typically fall into one of two categories: 1) true “pre-clinical” studies involving the use of MRI as a noninvasive disease monitoring tool which serves as a biomarker for selected aspects of the disease and 2) studies investigating the pathomechanism of known human MRI findings in CNS disease models. Most small animal MRI systems operate at 4.7–11.7 Tesla field strengths. Although the higher field strength clearly results in a higher signal-to-noise ratio, which enables higher resolution acquisition, a variety of artifacts and limitations related to the specific absorption rate represent significant challenges in these experiments. In addition to standard T1-, T2-, and T2*-weighted MRI methods, all of the currently available advanced MRI techniques have been utilized in experimental animals, including diffusion, perfusion, and susceptibility weighted imaging, functional magnetic resonance imaging, chemical shift imaging, heteronuclear imaging, and ¹H or ³¹P MR spectroscopy. Selected MRI techniques are also exclusively utilized in experimental research, including manganese-enhanced MRI, and cell-specific/molecular imaging techniques utilizing negative contrast materials. In this review, we describe technical and practical aspects of small animal MRI and provide examples of different MRI techniques in anatomical imaging and tract tracing as well as several models of neurological disorders, including inflammatory, neurodegenerative, vascular, and traumatic brain and spinal cord injury models, and neoplastic diseases.     

Spatial registration and normalization of images

This paper concerns the spatial and intensity transformations that map one image onto another. We present a general technique that facilitates nonlinear spatial (stereotactic) normalization and image realignment. This technique minimizes the sum of squares between two images following nonlinear spatial deformations and transformations of the voxel (intensity) values. The spatial and intensity transformations are obtained simultaneously, and explicitly, using a least squares solution and a series of linearising devices. The approach is completely noninteractive (automatic), nonlinear, and noniterative. It can be applied in any number of dimensions. Various applications are considered, including the realignment of functional magnetic resonance imaging (MRI) time-series, the linear (affine) and nonlinear spatial normalization of positron emission tomography (PET) and structural MRI images, the coregistration of PET to structural MRI, and, implicitly, the conjoining of PET and MRI to obtain high resolution functional images. © 1995 Wiley-Liss, Inc.     

Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the International League Against Epilepsy Neuroimaging Task Force

Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013‐2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the range of situations when detailed assessment is indicated. The Neuroimaging Task Force identified a set of sequences, with three‐dimensional acquisitions at its core, the harmonized neuroimaging of epilepsy structural sequences—HARNESS‐MRI protocol. As these sequences are available on most MR scanners, the HARNESS‐MRI protocol is generalizable, regardless of the clinical setting and country. The Neuroimaging Task Force also endorses the use of computer‐aided image postprocessing methods to provide an objective account of an individual's brain anatomy and pathology. By discussing the breadth and depth of scope of MRI, this report emphasizes the unique role of this noninvasive investigation in the care of people with epilepsy.     

Magnetic resonance imaging in psychiatry

Magnetic resonance imaging (MRI) is a relatively new radiological technique that may be useful in the study of psychiatric illness. MRI gives detailed structural information about the brain and also allows quantification of functional change. Current areas of study relevant to psychiatry include: schizophrenia, dementia, epilepsy and, to a lesser extent, alcohol and affective disorders. The authors review the basic principles of MRI, discuss the recent application to psychiatry, indicate its potential advantages and comment on the current limitations of this imaging modality.     

FDG-PET/MRI coregistration and diffusion-tensor imaging distinguish epileptogenic tubers and cortex in patients with tuberous sclerosis complex: a preliminary report

PURPOSE: Patients with tuberous sclerosis complex (TSC) are potential surgical candidates if the epileptogenic region(s) can be accurately identified. This retrospective study determined whether FDG-PET/MRI coregistration and diffusion-tensor imaging (DTI) showed better accuracy in the localization of epileptogenic cortex than structural MRI in TSC patients. METHODS: FDG-PET/MRI coregistration and/or DTI for apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were utilized in 15 TSC patients. Presurgery scalp EEG and postsurgery seizure control identified epileptogenic tubers (n = 27) and these were compared with nonepileptogenic tubers (n = 204) for MRI tuber volume, volume of FDG-PET hypometabolism on MRI coregistration, DTI, ADC, and FA values. RESULTS: Compared with nonepileptogenic tubers, epileptogenic regions had increased volume of FDG-PET hypometabolism (p < 0.0001), and increased ADC values in subtuber white matter (p < 0.0001). In contrast, the largest MRI identified tuber (p = 0.046) and decreased FA values (p = 0.58) were less accurate in identifying epileptogenic regions. Larger volumes of FDG-PET hypometabolism correlated positively with increased ADC values (p = 0.029), and localized to areas of cortical dysplasia adjacent to the tuber in four cases. CONCLUSIONS: Larger volumes of FDG-PET hypometabolism relative to MRI tuber size and higher ADC values identified epileptogenic tubers and adjoining cortex containing cortical dysplasia in TSC patients with improved accuracy compared with largest tuber by MRI or lowest FA values. Used in conjunction with ictal scalp EEG and interictal magnetoencephalography, these newer neuroimaging techniques should improve the noninvasive evaluation of TSC patients with intractable epilepsy in distinguishing epileptogenic sites for surgical resection.     

Workshop on Neurobiology of Epilepsy appraisal: New systemic imaging technologies to study the brain in experimental models of epilepsy

Modern functional neuroimaging provides opportunities to visualize activity of the entire brain, making it an indispensable diagnostic tool for epilepsy. Various forms of noninvasive functional neuroimaging are now also being performed as research tools in animal models of epilepsy and provide opportunities for parallel animal/human investigations into fundamental mechanisms of epilepsy and identification of epilepsy biomarkers. Recent animal studies of epilepsy using positron emission tomography, tractography, and functional magnetic resonance imaging were reviewed. Epilepsy is an abnormal emergent property of disturbances in neuronal networks which, even for epilepsies characterized by focal seizures, involve widely distributed systems, often in both hemispheres. Functional neuroimaging in animal models now provides opportunities to examine neuronal disturbances in the whole brain that underlie generalized and focal seizure generation as well as various types of epileptogenesis. Tremendous advances in understanding the contribution of specific properties of widely distributed neuronal networks to both normal and abnormal human behavior have been provided by current functional neuroimaging methodologies. Successful application of functional neuroimaging of the whole brain in the animal laboratory now permits investigations during epileptogenesis and correlation with deep brain electroencephalography (EEG) activity. With the continuing development of these techniques and analytical methods, the potential for future translational research on epilepsy is enormous. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here     

Tooth-Brushing Epilepsy: A Report of a Case with Structural and Functional Imaging and Electrophysiology Demonstrating a Right Frontal Focus

Summary: Patients with reflex epilepsies may provide insights into cerebral pathophysiology. We report a patient with an unusual form of reflex epilepsy in whom seizures are induced by tooth brushing. Magnetic resonance imaging (MRI) demonstrated a right posterior frontal low-grade tumor predominantly involving the precentral gyrus. Video-telemetry demonstrated right-sided epileptiform activity during a typical induced complex partial seizure. An ictal single photon emission computed tomography (SPECT) scan showed an area of hyperfusion that corresponded to the MRI lesion on coregistration with a surface-matching technique. A subsequent coregistered interictal SPECT scan demonstrated hypoperfusion in the same region. Ours is the first report to demonstrate a structural focus in this unusual form of reflex epilepsy. Possible mechanisms to explain the induction of the seizures are discussed.     

Coregistration of multimodal imaging is associated with favourable two‐year seizure outcome after paediatric epilepsy surgery

Aims. Multimodal coregistration uses multiple image datasets coregistered to an anatomical reference (i.e. MRI), allowing multiple studies to be viewed together. Commonly used in intractable epilepsy evaluation and generally accepted to improve localization of the epileptogenic zone, data showing that coregistration improves outcome is lacking. We compared seizure freedom following epilepsy surgery in paediatric patients, evaluated before and after the use of coregistration protocols at our centre, to determine whether this correlated with a change in outcome. Methods. We included paediatric epilepsy surgery patients with at least one anatomical and one functional neuroimaging study as part of their presurgical evaluation. Preoperatively designated palliative procedures and repeat surgeries were excluded. Multiple pre‐, peri‐, and postoperative variables were compared between groups with the primary outcome of seizure freedom. Results. In total, 115 were included with an average age of 10.63 years (0.12–20.7). All evaluations included video‐EEG (VEEG) and MRI. Seven (6%) had subtraction single‐photon emission CT (SPECT), 46 (40%) had positron emission tomography (PET), and 62 (54%) had both as part of their evaluation. Sixty (52%) had extratemporal epilepsy and 25 (22%) were MRI‐negative. Sixty‐eight (59%) had coregistration. Coregistered patients were less likely to undergo invasive EEG monitoring (p=0.045) and were more likely to have seizure freedom at one (p=0.034) and two years (p<0.001) post‐operatively. A logistic regression accounting for multiple covariates supported an association between the use of coregistration and favourable post‐surgical outcome. Conclusions. Coregistered imaging contributes to favourable postoperative seizure reduction compared to visual analysis of individual modalities. Imaging coregistration is associated with improved outcome, independent of other variables after surgery. Coregistered imaging may reduce the need for invasive EEG monitoring, likely due to improved confidence in presurgical localization. These findings support the use of multimodal coregistered imaging as part of the presurgical assessment in patients evaluated for surgical treatment of intractable epilepsy.     

High resolution Magnetic Resonance Imaging of the rat spinal cord

Abstract

A two turn saddle shaped surface coil receiver was developed that allowed high resolution magnetic o resonance imaging of the rat spinal cord. This is particularly important in laboratory animals where central nervous system regions of interest are relatively small. A continuous copper wire 1.5 mm in diameter was wound into two turns 28 mm in diameter. The saddle shape of the second turn improved the homogeneity of the signal within the region of interest and maintained sufficient field of view and depth of penetration. The quality factor (Q) for the surface coil was Q= 199 unloaded, and Q=60 loaded. Using this surface coil with a GE CSI II 2.0 Tesla small bore magnet, spin echo T1 (TR= 500 msec, TE=25 msec) and T2 (TR=2000 msec, TE= 100 msec) weighted images were obtained in cross section, using 2 mm slice thickness with 2 excitations per phase encoding step. A sagittal gradient echo (rapid scan, TR=85 msec, TE= 10 msec) was used to document reestablishment of vascular flow following ischemia. Spinal cord ischemia was induced by 14 minute temporary occlusion of spinal cord blood supply. MRI was performed at 18 hours following ischemia. There was a 1.4 fold increase in T2 image intensity in ischemic rat spinal cord (\i = 4), consistent with edema formation, compared to normal rat spinal cord (n = 4). Preliminary studies show that similar high resolution images can be performed on the rat brain. This technique uses standard MRI equipment and the surface coil is made from inexpensive readily available materials. There are various animal models of cerebral and spinal cord injury that would benefit from improved high resolution MRI. This coil design may have application in larger animal models and the clinical setting. [Neurol Res 1996; 18: 471-474]     

Magnetic Resonance Spectroscopy in Animal Models of Epilepsy

Summary:  The noninvasive localization of the epileptogenic zone continues to be a challenge in many patients that present as candidates for possible epilepsy surgery. Magnetic resonance imaging (MRI) techniques provide accurate anatomical definition, but despite their high resolution, these techniques fail to visualize the pathological neocortical and hippocampal changes in a sizable number of patients with focal pathologies. Further, visualized lesions on MRI may not all produce seizures. One of the keys to the understanding of the epileptogenic zone lies in the recognition of the metabolic alterations that occur in the setting of epileptic seizures. Magnetic resonance spectroscopy (MRS) is a valuable tool that can be used to study the metabolic changes seen in both acute and chronic animal models of epilepsy. Such study allows for the identification of epileptic tissue with high sensitivity and specificity. We present here a review of the use of MRS in animal models of epilepsy.     

Introduction to PET imaging with emphasis on biomedical research

Medical imaging is migrating from anatomic imaging to functional imaging and fused anatomic/functional imaging. The technology is being adapted for biomedical research using both clinical and small animal scanners. The ability to externally image real-time physiologic processes in both normal and deranged conditions, including various models to image gene expression, apoptosis, or drug biodistribution, has powerful impact on the exploration of biomedical and fundamental biological research. Positron emission tomography (PET) has a unique ability to not only provide such images but also to do so with high resolution (typically 1-2mm resolution for small animal scanners) and to provide both relative and absolute quantitation. This technology is revolutionizing biomedical and biological research. This article reviews the underlying principles involved in this technology, gives a brief history of its development, and then introduces the interested researcher to some of the important techniques that could be of use.     

Functional MRI Studies of Animal Models in Epilepsy

Summary:  Functional magnetic resonance imaging (fMRI) has become a widely used imaging modality in the past decade in both human studies and animal models. Epilepsy presents unique challenges for neuroimaging due to subject movement during seizures, and the need to correlate the timing of often unpredictable seizure events with fMRI data acquisition. These challenges can readily be overcome in animal models of epilepsy. Animal models also provide an opportunity to investigate the fundamental relationships between fMRI signals and brain electrical activity through invasive studies not possible in humans. fMRI studies in animal models of epilepsy can enable us to correctly interpret fMRI signal increases and decreases in human studies, ultimately elucidating specific networks that will be targeted for improved treatment of epilepsy.     

Magnetoencephalography and magnetic source imaging in children

Magnetoencephalography is a technique that detects the magnetic fields associated with the intracellular current flow within neurons, unlike electroencephalography, which measures extracellular volume currents. Superconducting quantum interference devices are used to amplify these very small magnetic field signals. Magnetic source imaging is the combination of functional data derived from magnetoencephalographic recordings coregistered with structural magnetic resonance imaging (MRI). The utility of magnetic source imaging lies in the combination of the submillisecond temporal resolution of magnetoencephalography with the precise anatomic images provided by magnetic resonance imaging. As such, magnetic source imaging is a useful tool for noninvasive localization of the epileptogenic zone in children who are candidates for epilepsy surgery. Similarly, using magnetoencephalographic recordings with evoked and event-related potentials, magnetic source imaging holds great promise as a noninvasive method for precise localization of somatosensory, motor, language, visual, and auditory cortex. Finally, magnetic source imaging is proving a valuable research tool in the investigation of epilepsy, head trauma, brain plasticity, and disorders of language, memory, cognition, and executive function in children.     

Positron emission tomography imaging in gliomas: applications in clinical diagnosis,for assessment of prognosis and of treatment effects,and for detection of recurrences

Neuroimaging plays a significant role in the diagnosis of intracranial tumours, especially brain gliomas, and must consist of an assessment of location and extent of the tumour and of its biological activity. Therefore, morphological imaging modalities and functional, metabolic or molecular imaging modalities should be combined for primary diagnosis and for following the course and evaluating therapeutic effects. Magnetic resonance imaging (MRI) is the gold standard for providing detailed morphological information and can supply some additional insights into metabolism (MR spectroscopy) and perfusion (perfusion‐weighted imaging) but still has limitations in identifying tumour grade, invasive growth into neighbouring tissue and treatment‐induced changes, as well as recurrences. These insights can be obtained by various positron emission tomography (PET) modalities, including imaging of glucose metabolism, amino acid uptake and nucleoside uptake. Diagnostic accuracy can benefit from coregistration of PET results and MRI, combining high‐resolution morphological images with biological information. These procedures are optimized by the newly developed combination of PET and MRI modalities, permitting the simultaneous assessment of morphological, functional, metabolic and molecular information on the human brain.     

New Techniques in Magnetic Resonance and Epilepsy

Summary: Developments in magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and single photon emission tomography (SPECT) have opened new opportunities for noninvasive brain investigation. Functional imaging methods involving noninvasive MRI and minimally invasive PET and SPECT are available that allow investigation of brain abnormality in intractable epilepsy patients. Noninvasive techniques enable the investigation of many aspects of the underlying neuropathologic basis of intractable seizures and of the relationship of functional abnormalities both to structural abnormalities and to the seizure focus. New MRI techniques demonstrate the structure of the brain in fine detail (especially the hippocampus), provide information about the underlying metabolism of brain regions, and demonstrate functional activity of the brain with high spatial and temporal resolution. The clinical impact of this noninvasive information cannot be overstated and these techniques provide indispensable information to neurologists specializing in epi-leptology. The proper use and interpretation of the findings provided by these new technologies will be a major challenge to epilepsy programs in the next few years.     

The role of magnetoencephalography in "nonlesional" epilepsy

The surgical management of neocortical epilepsy is challenging because many patients are without obvious structural lesions, or lesions are small and easily overlooked during routine clinical interpretation of magnetic resonance imaging (MRI) data. Even when functional imaging data suggest focal epileptiform pathology, in the absence of a concordant structural lesion, invasive monitoring is often required to confirm that an appropriate surgical target has been identified. This study sought to determine the extent to which knowledge of magnetoencephalography (MEG) data can augment the MRI-based detection of structural brain lesions. MRI and whole-head MEG data were obtained from 40 patients with neocortical epilepsy. As a result of MEG data, 29 cases were sent for MRI reevaluation. In seven of these cases, MEG-guided review led to specification of now clear, but previously unidentified, lesions. There were two additional cases for which follow-up high-resolution imaging did not confirm structural abnormalities. In patients with neocortical epilepsy, MEG is a useful adjunct to MRI for the identification of structural lesions.     

Development of Hippocampal Atrophy: A Serial Magnetic Resonance Imaging Study in a Patient Who Developed Epilepsy After Generalized Status Epilepticus

Summary: Purpose : To investigate changes in hippocampal volume.
Methods : We used serial magnetic resonance imaging (MRI) in a patient who developed chronic epilepsy after having generalized tonic-clonic status epilepticus (SE). Five MRI investigations were performed during SE and a 58-month follow-up period. Hippocampal volumetric measurements and coregistration of scans were performed to detect hippocampal atrophy.
Results : During status both mesiotemporal regions returned a high signal on T,-weighted images. Two months after the onset of SE, bilateral hippocampal atrophy was detected. Further progressive hippocampal atrophy was detected in the subsequent 58 months by both hippocampal volumetric measurements and coregistration of scans.
Conclusions : Our findings suggest that hippocampal atrophy is a process that may continue after the end of the SE.     

Diffusion-based magnetic resonance imaging and tractography in epilepsy

Diffusion-based imaging is an advanced MRI technique that is sensitive to the movement of water molecules, providing additional information on the micro-structural arrangement of tissue. Qualitative and quantitative analysis of peri, post and interictal diffusion images can aid the localization of seizure foci. Diffusion tensor tractography is an extension of diffusion-based imaging, and can provide additional information about white matter pathways. Both techniques are able to increase understanding of the effects of epilepsy on the structural organization of the brain, and can be used to optimize presurgical planning of patients with epilepsy. This review focuses on the basis, applications, limitations, and future directions of diffusion imaging in epilepsy. Literature search strategy: We searched Pubmed using the terms "diffusion MRI or diffusion tensor MRI or tractography and epilepsy."