Epilepsy is one of the most common neurologic disorders and restricts the quality of life in affected individuals (Hirtz et al., 2007). New cases of epilepsy are most prominent among children. Antiepileptic drug therapy is effective in approximately two thirds of cases, implying that one-in-three do not obtain good seizure control or have unacceptable side effects from medications. Surgery to remove epileptogenic brain tissue is a good option for children (and adults) whose seizures cannot be controlled with medications. One key to successful surgery is to determine the spatial relationship between the seizure focus and functionally important pathways such as primary motor areas controlling movement. The precise delineation and sparing of these areas prevents postoperative motor deficits.
The current gold standard for identifying primary motor areas in human brain is electrical stimulation mapping (ESM), which, however, is invasive and often not adequately sensitive in young children (Wyllie & Awad, 1991; Haseeb et al., 2007; Lesser et al., 2010). A noninvasive imaging technique using functional magnetic resonance imaging (fMRI), that measures blood oxygen level–dependent (BOLD) contrast while tasking motor functions, has demonstrated great promise as a viable alternative to ESM (Ruge et al., 1999; Schlosser et al., 1999; Roessler et al., 2005; Kho et al., 2007; de Ribaupierre et al., 2012). Although fMRI has been used widely for preoperative planning and decision-making (Medina et al., 2005; Nimsky et al., 2005; Roessler et al., 2005; Kho et al., 2007; de Ribaupierre et al., 2012), it is challenging to perform fMRI studies in infants and young patients with neurologic conditions, who are uncooperative or unable to follow task instructions during the study (Berntsen et al., 2008; Rumpel et al., 2009; Wengenroth et al., 2011; Grabski et al., 2012). Furthermore, the fMRI technique is inherently unable to localize crucial white matter structures, which may be at risk for damage or resection during surgery.
Diffusion-weighted imaging (DWI) is a powerful technique that requires only limited patient cooperation and may be used to investigate white matter tracts (Basser et al., 1994; Basser, 1995; Conturo et al., 1999; Mori et al., 1999; Basser et al., 1994; Mori et al., 2000), such as corticospinal tract (CST) which, if damaged, would result in deficits of contralateral motor function (Nimsky et al., 2005). However, none of the previous studies on clinical DWI have reported on corticobulbar tract (CBT) that is distinctly connected to the inferior precentral gyrus and primarily executes control of movement of the mouth/lip. The reason for this is presumably due to the intravoxel problem of multiple crossing fibers at a voxel making it difficult to track this pathway (Alexander et al., 2001; Kinoshita et al., 2005; Mikuni et al., 2007; Qazi et al., 2009; Singh & Wong, 2010). We have recently developed a new tractography method combining independent component analysis and ball–stick model (ICA+BSM tractography) in order to isolate separate diffusion tensors of CBT, CST, arcuate fasciculus, and superior longitudinal fasciculus from each other and from other fiber tracts. Compared with postmortem histology, the ICA+BSM tractography achieved an accuracy of 92.2% for reconstruction of CBT/CST derived from clinical DWI data (Jeong et al., 2012). This new approach has been applied in the present study.
The goals of the present study were to compare primary motor areas of the ICA+BSM method with ones of fMRI and ESM. We hypothesized that the termination of CBT/CST pathways at the cortex delineated by the ICA+BSM tractography would be concordant with fMRI- and ESM-defined motor areas of “mouth/lips,” “fingers,” and “ankle/leg.” In addition, group analyses of “mouth/lip,” “finger,” and “leg” pathways were used to develop in vivo stereotaxic probability maps of “mouth/lip,” “finger,” and “leg” motor areas. Based on the resulting probability maps, a maximum a posteriori probability (MAP) classifier (DeGroot, 1970) was designed to automatically predict individual CBT/CST pathways. Thereby, a systematic leave-one-out approach was employed to avoid a circular analysis in evaluating the performance of DWI-MAP classification. Likewise, the DWI-MAP classifier was tested to predict the pathways of “mouth/lip,” “fingers,” and “leg” in children with focal epilepsy. The prediction accuracy was compared with extraoperative ESM.
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- Supporting Information
This diffusion MRI study is a preliminary examination of the clinical feasibility of a new fiber tractography technique for simultaneous localization of cortical areas of primary motor functions and their underlying white matter tracts for presurgical planning in children with intractable focal epilepsy. The study provides the promising method to localize the primary motor areas in clinical cases where neither fMRI nor ESM is easy to employ. The results obtained from this study have important implications for presurgical planning of infants or young children with focal epilepsy or other neurologic conditions, without any extra cost of other imaging modalities.
The principle of presurgical evaluation for epilepsy is to determine the spatial relationship between the epileptogenic zone and functionally important cortex. Without accurate localization of such brain regions, one cannot accomplish the ultimate goal of epilepsy surgery, which is to eliminate the recurrence of epileptic seizures without creating new sensorimotor or cognitive deficits. The current gold standard to identify the motor cortex is direct ESM (Wyllie & Awad, 1991; Haseeb et al., 2007; Lesser et al., 2010). Yet, stimulation is not an ideal gold standard method, since it carries the inherent risk of electrically induced seizures, and sometimes fails to identify the motor cortex in children (Haseeb et al., 2007). An alternative approach is fMRI, which is highly susceptible to movement artifacts and demands cooperation of the patient during scanning; thus, fMRI is difficult to apply to young children with epilepsy (Berntsen et al., 2008; Rumpel et al., 2009; Wengenroth et al., 2011; de Ribaupierre et al., 2012; Grabski et al., 2012). Because the epileptogenic zone sometimes involves the bottom of a deep sulcus (Besson et al., 2008), a functional brain mapping modality capable of identifying the origin and course of functionally important pathways is highly desirable.
To overcome the limitations of currently available motor mapping modalities, the present study hypothesized that a new diffusion tractography method called “ICA+BSM” can serve as a tool to accurately visualize CST projections to mouth/lip, finger, and ankle/leg motor areas. The present study examined the intersubject variation (or reproducibility) of the ICA+BSM by introducing the homunculus representation of mouth/lip, finger, and leg pathways using clinical DWI with a small number of gradient directions and low b-value. The resulting homunculus maps of primary motor pathways were then applied to design an objective classifier that detects the CBT and CST pathways terminating at the cortices of mouth/lip, finger, and leg areas. The cortices at the origin of mouth/lip, finger, and leg pathways were finally compared with both fMRI and ESM findings. The results indeed demonstrated the reliability of ICA+BSM tractography as compared to noninvasive fMRI and invasive ESM.
A critical assumption of this approach is that no significant reorganization took place in the development of CST pathways in children with focal epilepsy, implying that the CST variability in children with focal epilepsy is within that in healthy controls. In addition, the present study assumes that the end of CTS pathways should contain the motor cortex in children even with structural lesions. This critical assumption may limit the accuracy of DWI-MAP classifier in children with large lesions (such as hemimegalencephaly or perisylvian polymicrogyria) that may reorganize the CST. The current study is not designed to validate the DWI-MAP classification in such extreme cases, which very rarely undergo extraoperative ECoG recording. Under the assumption that the end of CST pathways should contain the motor cortex, the DWI-MAP classification utilizes the conditional probability maps estimated from fMRI data of normal children. Although fMRI includes vascular in-flow artifacts providing low specificity (Schlosser et al., 1999), our preliminary results suggest that the fMRI-driven conditional probability maps are effective to localize primary motor areas. The proposed DWI-MAP classifier achieved accurate localizations comparable to ESM. If sufficient cases are available, one could investigate how the performance of DWI-MAP classifier is affected by the size and location of pathologic lesions or reorganization in patients with focal epilepsy.
Another major challenge to the present study was the potential error in registration of ESM and MRI to assess the accuracy of the proposed DWI-MAP classifier. To minimize interoperator errors in registering ESM to MRI, future studies might use a new registration method based on surface-warping algorithms. The sulcus and electrodes in a two-dimensional digital picture will be detected by applying a conventional active contour model and then registering to a sagittal plane of three-dimensional rendered MRI using fast diffeomorphic landmark-free surface registration (Yeo et al., 2010). This registration scheme may ensure better localization using the DWI-MAP classifier with ESM based on the cortical homunculus map. Because the present study relies on a priori knowledge constructed from fMRI (or ESM), our DWI method may not able to detect deeper portions of the tract for which fMRI (or ESM) may be limited in detecting associated functions. Reduced accuracy for the tracts associated with the leg area may be caused by their deeper position, suggesting that the present approach may be effective only for cortical activation using fMRI or stimulation to the proximity/termination of tracts. It should be noted that large subdural electrodes cannot be placed on the medial surface of the rolandic area due to the presence of large bridging veins; therefore, lower accuracy in finding the leg motor areas may be partly attributed to sampling errors on the gold-standard ESM approach. Future studies should examine this effect more carefully with other potential confounds such as age, gender, and the scanner type itself.
In conclusion, a novel DWI-MAP classification using ICA+BSM showed promise to perform simultaneous localization of cortical areas and white matter pathways associated with important motor functions. This preliminary study demonstrated that our method objectively discriminated the lateral-medial CST pathways originating from mouth/lip, finger, and leg areas, which are clinically important to plan resective epilepsy surgery in patients with focal epilepsy, and further assess the degree of motor deficit associated with abnormal gray–white matter in patients with other neurologic conditions. By combining DWI-MAP classification with fMRI and ESM, we present new insights as to how white matter tractography may be used to delineate lateral-medial CST pathways in patients who are uncooperative or not able to follow task instructions in clinical studies. In summary, the significance of the present study for presurgical planning in epilepsy patients includes the following: (1) no added risk, (2) no requirement of patient cooperation, (3) high sensitivity to identify the motor cortex even in young children, (4) capability to trace the course of different motor pathways, and (5) may be useful for other types of neurosurgical procedures (i.e., tumor resection).