This study is being done to look at the relationship between brain structure and brain function in patients with epilepsy or focal brain lesions (abnormal areas) that require surgery. This study will look at an imaging technique called magnetic resonance imaging (MRI) for looking at the brain. Specifically, the study will look at functional MRI, which is an imaging technique that can map brain function by taking pictures of the brain as it performs different tasks such as reading, thinking, or moving a body part and diffusion tensor imaging (DTI), which will look at brain structure. These types of imaging may help us learn more about different areas of the brain and how those areas of the brain are used in children with epilepsy and/or focal brain lesions.

This study will compare functional MRI to other tests that are used to evaluate brain function. This study will also look at any relationships between brain structure and brain function using MRI. We plan to study 30 children with epilepsy and/or focal brain lesions and up to 20 children without epilepsy or brain lesions between the ages of 4 and 21 in this study.

Future participation as one of the sites in the multi-center trial for fMRI Mapping in Childhood Epilepsy, lead by William Gaillard, M.D., P.I. at Children’s National Medical Center is anticipated. The data for the fMRI portion proposed in this study will be shared with the other sites participating in the multi-center trial by complying with the federal regulations for data sharing.

When individuals are identified for this part of the study, a screening questionnaire and consent and assent forms will be completed. Participants will be brought to Children’s Healthcare of Atlanta at Scottish Rite where they will first complete a training for the tasks to be completed during the imaging session. They will then participate in the imaging session, which will be performed in a 1.5 Tesla clinical MRI system at Children’s Healthcare of Atlanta at Scottish Rite. The imaging session will provide information on brain structure, activation in specific areas of the brain and connectivity. The full visit (training and imaging) should be completed in about one hour. Participants in the “normal volunteer” group will receive $50 as compensation for this study.

Introduction

Background and Significance • Functional MRI Surgical treatment is being used with increasing frequency for patients with intractable epilepsy. The success of this operation largely depends on the results of a comprehensive pre-operative patient evaluation with the main purpose of delineating the epileptogenic lesion. The pre-operative assessment includes video EEG monitoring, structural neuroimaging (i.e. MRI), functional cerebral imaging such as SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) which are capable of localizing epileptogenic foci, and neuropsychological evaluation. The more results of these localization techniques that coincide to a single epileptogenic focus, the greater the likelihood for a successful surgical outcome. In the preoperative evaluation of surgical candidates, a unique neuropsychological evaluation called the Wada test is performed. The Wada test includes standard neuropsychological assessment and intracarotid sodium amytal testing, to have the capability of predicting hemispheric lateralization of language and memory and sometimes helping with localization of a brain lesion based on cognitive function and dysfunction [1]. The Wada test is usually used to determine the cerebral speech dominance, to predict postsurgical amnesia and is found to be useful in predicting laterality of seizure focus in candidates for temporal lobectomy. However, the Wada test is invasive, requiring an angiogram. In the mean time, functional magnetic resonance imaging (fMRI) has been proven to have potential as a possible non-invasive alternative method for lateralizing the language and motor networks, and to a lesser degree – memory, in cooperative children with epilepsy [2-4]. Functional MRI also provides an opportunity to follow the post-lesional or post-surgery plasticity of these networks using repeated examinations in a same patient, such that fMRI may also contribute additional useful information in the pre-surgical planning and post-surgical monitoring. Therefore, the effectiveness and the reliability of fMRI in epilepsy patients compared to Wada test (in those patients where the Wada test is deemed clinically relevant) would be very helpful in assessing the clinical utility of fMRI in epilepsy patients.

Another patient population where presurgical MR imaging evaluation is performed are children with focal brain lesions. It is important to know where eloquent cortex lies in relationship to these abnormalities as well as identifying important anatomic structures. Performing advanced imaging evaluation of pediatric neurosurgical candidates provides greater insight to the nature of the abnormality that is present and offers guidance for the neurosurgeon in the removal of the lesion as safely as possible.

A number of studies have shown that fMRI language tasks reliably identify language areas in presurgical patients, but activation using single paradigms sometimes may disagree with the Wada test [5-9]. For instance, most studies report partial disparity with Wada test in 10 to 15% of studies [10]. Therefore, the hope for fMRI as a means to replace Wada test for language lateralization is hampered. A likely source of those occasional discrepancies is that language activation tasks, for both Wada test and fMRI, target only the limited aspects of language processing. Using two or more tasks could provide a better representative view of language laterality by mapping multiple language functions [10]]. By doing that, we should be able to ascertain whether a series of tasks confirm findings, improve rater reliability, and increase agreement with Wada test (in those patients where Wada is deemed clinically relevant). In this study, we will employ tasks designed to identify anterior “expressive” networks in inferior frontal gyrus (IFG), implicated in word retrieval, and middle frontal gyrus (MFG), implicated in verbal working memory. We also will use tasks to identify “receptive” areas along the left superior temporal sulcus implicated in whole-language comprehension. Furthermore, tasks were designed so that at least two tasks targeted similar language/processing functions and regions.

• Diffusion Tensor Imaging The second imaging technique to be employed in this project is diffusion tensor imaging, which provides a quantitative measure of the microstructure of organized tissue as well as the direction of this organization. In organized tissue such as brain white matter and muscle, diffusion of water is orientation dependent. In the past decade, the development of diffusion tensor imaging with MRI has made it possible to quantitatively map this anisotropy noninvasively, providing a unique means for studying tissue orientation and microstructural integrity in vivo [11-13]. Although there are a number of possible contributions to the diffusion anisotropy [14], its measurement has been applied to many in vivo applications because of it being now well established that the MR measurement of the effective diffusion tensor in tissues can provide unique biologically and clinically relevant information that cannot be provided by other imaging methods. The most interesting application of DTI lies in the study of brain white matter.

Because of the sensitivity of DTI in detecting degradations of microstructural integrity of white matter, it is natural to apply DTI to the study of neurological pathways of language networks in the patients with intractable epilepsy. The focus of the DTI work in this study will be to evaluate the white matter of neural circuits serving the regulation of language processing and compare it with that in the region of counter lateral side of the brain. Thus, the areas to be focused on in this study will include white matter tracts between Broca’s and Wernicke’s areas on the dominant side of language compared to the counter lateral side. The analysis of DTI data mostly relied on measurements in ROIs defined using a priori knowledge. DTI will also be used to identify major white matter tracts in order to evaluate their involvement by the abnormality being investigated and to provide a map for the neurosurgical approach for lesion resection.

Future participation as one of the sites in the multi-center trial for fMRI Mapping in Childhood Epilepsy, lead by William Gaillard, M.D., P.I. at Children’s National Medical Center is anticipated. The data for the fMRI portion proposed in this study will be shared with the other sites participating in the multi-center trial by complying with the federal regulations for data sharing.

Objectives:

Objective 1. Investigate the responses of brain functions to fMRI tasks targeting different aspects of language processing to ascertain whether these tasks confirm findings and result in agreement with Wada test (in those patients where the Wada test is deemed clinically relevant). Our hypothesis is that a panel of fMRI tasks targeting different aspects of language processing increases accuracy in determining hemisphere language dominance.

Objective 2. Examine the relationship between the specific language deficits and brain morphology. To examine these relationships, we will utilize an imaging protocol that will include evaluation of brain structure and connectivity in white matter tracts using diffusion tensor imaging (DTI).

Objective 3. Investigate the responses of brain functions to fMRI tasks stimulated by motor left/right finger tapping to assist the evaluation of the geometric relationship between left/right motor cortex and seizure foci identified by SPECT. The hypothesis is that the result of this evaluation should be helpful in surgical planning for the epilepsy patients and focal brain lesion neurosurgical candidates.

Methods and Materials

Human Subjects: 30 patients with intractable epilepsy and/or focal brain lesions and up to 20 normal volunteers, ranging in age from 4 to 21 years, will participate with fMRI language paradigms, fMRI motor mapping, and diffusion tensor imaging (DTI). Patients requiring sedation for scanning will be excluded from the study.

Prior to the evaluations summarized in this protocol, the patients recruited for this study will undergo the regular pre-surgical neuropsychological tests, and the Wada test where appropriate. The Wada test will be limited to those patients where the test is deemed clinically relevant and ordered as standard of care.

Neuroimaging:

The MRI experiments will be performed on a 1.5T Siemens scanner located at CHOA’s Scottish Rite campus equipped with an array head coil. Anatomical and DTI sequences are already established on this scanner and preliminary fMRI data has been acquired. Fast imaging sequences, using echoplanar methods, will be used to enable the high temporal resolution necessary for fMRI. In addition to the functional scans, a series of conventional anatomic scans will be obtained for each participant, which will allow the subsequent superposition of functional data with anatomy. The scan will include structural MRI, fMRI while a series of cognitive (language) tasks and motor tasks are performed, and then the DTI. All scans should be completed in 30-60 minutes.

Functional MRI: fMRI images will be acquired using a single-shot T2*-weighted EPI. During the gradient EPI scanning, the stimuli will be used to activate the particular brain function. A multi-task stimulation paradigms using a block design approach, including listening, reading, semantic decision, and verbal fluency tasks, will be applied in order to increase the confidence level of the lateralization of the language function. The tasks include a response element and the response is monitored using a button box. For all the tasks, the subjects do not talk during MR scanning to avoid motion artifacts. When a task requires reading or answering, the subjects should do it silently without moving head or mouse as best as they can. The subjects understanding of the task will be validated by analysing the responses from the button box. For those children with epilepsy selected for this study, they will be divided into four age groups (4-6, 7-9, 10-12, 12+). The difficulty level of the tasks will be selected before the experiment, which is proportionally corresponding to the age group that the child belongs.

Task 1. Listening to a story Task 2. Reading a Story Task 3. Auditory description task (ADT) – Semantic Decision Task 4. Auditory Category Task (Autcat or AC) – Verbal Fluency

For the motor tasks a series of cognitive tasks (left and/or right finger tapping) will be performed.

Diffusion Tensor Imaging: DTI is becoming a widely available and used technique for studying white matter integrity in the brain. While it is possible to perform tract-tracing based on diffusion tensor data, results are still not adequately reliable for routine applications. Thus, our approach will utilize mainly the magnitude of anisotropy, particularly fractional anisotropy in this study. Many studies (e.g. (Lim and Helpern 2002)) using anisotropy measurement to ascertain microstructural degradation in various neurological and psychiatric diseases have been reported. In this study, we will perform the DTI imaging of the whole brain and use ROI-based analysis of fractional anisotropy to ascertain differences in white matter integrity about language networks between different subjects with intractable epilepsy. Using this DTI method we will also identify major white matter fiber tracks that are important to visualize for neurosurgical planning.

The diffusion tensor images will be acquired with a single-shot EPI sequence with diffusion weighting applied in 12 directions. The DTI data set will be transferred onto a workstation where software for DTI post-processing is installed for diffusion tensor calculation on a pixel-by-pixel basis. Based on the diffusion tensor information, fractional anisotropy (FA) maps will be generated to reveal the degree of directional dependence of the diffusion in brain tissue (FA=1 when diffusion is purely anisotropic and FA=0 when diffusion is purely isotropic) and maps of the apparent diffusion coefficient (ADC) will also be calculated. In order to visualize white matter tracts, the principal eigenvector associating with the maximum eigenvalue will be used to obtain the projections along x, y, z directions in lab frame, respectively, which will be color coded and displayed to represent the orientation of white matter tracts. ROIs along the language networks/pathways will be defined based on the anatomical knowledge as well as the results from functional connectivity study. Average FA and ADC in the ROIs will be calculated and compared with the counter lateral side of the brain and with different subject in the analysis.

Data Analysis: The image data will be transferred to a PC in a locked room and will require a password to access the data in order to protect patients’ confidentiality. The image data will be analyzed using the software installed on PC to obtain the fMRI and DTI results. The original image data will also be encoded and de-identified, and then sent to Central Storage and Processing to be accessed by all sites who participate in the multi-center trial as referenced earlier.

Potential risks and discomforts: Potential risks associated with this participation in the research project are minimal.

Imaging procedures. There are four parameters that are considered as potential risks in a MR study: (a) static magnetic field strength, (b) rate of change of magnetic field (dB/dt), (c) RF power desposition, and (d) acoustic noise level. On the 1.5 T clinical systems which will be used for these studies, all of these parameters are kept within the FDA limits and do not pose a significant risks.

As mentioned above, there are no known risks associated with the MRI procedure although there may be some risks that are not known. The magnet makes a loud pinging sound; however, earphones are worn during the procedure to muffle this sound and to allow the technician to communicate with the participant during the procedure. Because the magnetic field affects any metallic object, participants cannot be included if they have any type of metallic implant in the body, including pacemakers, aneurysm clips, shrapnel, metal fragments, orthopedic pins, screws or plates, IUDs or body piercings that cannot be removed. The risks associated with these objects (that they may heat up or move) are discussed with the potential participants when they are screened.

There are also minor discomforts encountered by some participants during the procedure, including muscle discomfort from lying still in the scanner, or becoming too hot or cold due to the ambient temperature of the room. Some people become claustrophobic in the scanner. Others experience a feeling of dizziness in response to the strong magnetic field (see above). These possibilities are explained to participants and they are requested to ask the staff for help if they are uncomfortable. Participants are informed that they are free to stop the procedure at any time.

All the medical tests and neuropsychological procedures pre- or post- imaging studies involved in this research project are regular routine medical procedures that will be conducted at Children’s Healthcare of Atlanta at Scottish Rite. The questionnaires before the imaging session do not involve risk to the participants.

Schedule and Procedures:

A total of 30 patients and up to 20 normal volunteers will participate this research study. Before the imaging session, a screening questionnaire will be administered and an informed consent/assent procedure will be completed. Participants in the “normal volunteer” group will be reimbursed $50 for their time and other expenses associated with participation. The schedule of procedures for the neuroimaging is as follows:

1. Transportation. The participants should provide their own transportation to Children’s Healthcare of Atlanta at Scottish Rite where the MRI scan will take place.
2. Task training. Before the imaging procedures, participants will complete a training session on the tasks they will be asked to complete while in the scanner. This is a computer-based training program; training to criterion should take less than one hour. When training is complete, the participants will be taken to the MRI suite for the MRI scan.
3. Head Scanning: The structural magnetic resonance imaging (sMRI), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) will be performed on a Siemens 1.5T clinical scanner at Children’s Healthcare of Atlanta at Scottish Rite. An array head coil will be used to collect the MR data. Fast imaging sequences, using echoplanar methods, will be used to enable the high temporal resolution necessary for fMRI. A series of conventional anatomic scans will be obtained for each participant, which will allow the subsequent superposition of functional data with anatomy.
4. Tasks: While the fMRI is being performed, the participants will be asked to perform a series of cognitive tasks assessing language and motor function. Audio and visual stimuli will be presented and participants will respond by pressing a button. Images will be projected on a PC interfaced to a long focal length projector. These images will thus be projected into the magnet bore and will be visible to the participant via a small mirror on the head holder. Responses will be acquired with a fiber optic button response box interface to the computer. The fiber optic box allows response acquisition without the generation of electromagnetic noise in the scanner. All scanning will be completed in 30-60 minutes,

Inclusion Criteria:

• children with intractable epiilepsy
• children with focal brain lesion(s)

Exclusion Criteria:

• children requiring sedation for scanning