Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited

Tractography based on diffusion-weighted MRI (DWI) is widely used for mapping the structural connections of the human brain. Its accuracy is known to be limited by technical factors affecting in vivo data acquisition, such as noise, artifacts, and data undersampling resulting from scan time constraints. It generally is assumed that improvements in data quality and implementation of sophisticated tractography methods will lead to increasingly accurate maps of human anatomical connections. However, assessing the anatomical accuracy of DWI tractography is difficult because of the lack of independent knowledge of the true anatomical connections in humans. Here we investigate the future prospects of DWI-based connectional imaging by applying advanced tractography methods to an ex vivo DWI dataset of the macaque brain. The results of different tractography methods were compared with maps of known axonal projections from previous tracer studies in the macaque. Despite the exceptional quality of the DWI data, none of the methods demonstrated high anatomical accuracy. The methods that showed the highest sensitivity showed the lowest specificity, and vice versa. Additionally, anatomical accuracy was highly dependent upon parameters of the tractography algorithm, with different optimal values for mapping different pathways. These results suggest that there is an inherent limitation in determining long-range anatomical projections based on voxel-averaged estimates of local fiber orientation obtained from DWI data that is unlikely to be overcome by improvements in data acquisition and analysis alone.The creation of a comprehensive map of the connectional neuroanatomy of the human brain would be a fundamental achievement in neuroscience. However, despite the numerous efforts to date (for a historical review, see ref. 1), creating this map remains a challenge. A major limitation is that the current gold-standard technique for mapping structural connections, which requires the injection of axonal tracers, cannot be used in humans. The introduction of diffusion-weighted MRI (DWI) (2–4) and the subsequent advent of diffusion tensor MRI (DTI) (5) opened the possibility of exploring the structural properties of white matter in the living human brain (6). Local DWI measures are used clinically for the early detection of stroke and for the characterization of neurological disorders such as multiple sclerosis, epilepsy, and brain gliomas, among others (7). In addition, tractography approaches (8–12) that can infer structural brain connectivity based on brain-wide local DWI measurement have been developed (for reviews, see refs. 13 and 14). The success of DWI tractography as a method for studying fiber trajectories has led to a systematic characterization of large white-matter pathways of the living human brain (e.g., ref. 15), and now it is used routinely to provide a structural explanation for aspects of human brain function (16).A major limitation of DWI tractography is that its characterization of axonal pathways is based on indirect information and numerous assumptions. Local white matter orientation profiles are based on the statistical displacement profile (i.e., diffusion propagator) of water molecules in brain tissue on the coarse scale of a voxel, and fiber trajectories are inferred based on the adjacency of similar diffusion profiles. This approach differs fundamentally from conventional tract-tracing approaches in animals, which involve the physical transport of traceable molecules through the cells’ axoplasm over a large distance. Because these molecules occupy positions within the axon, it sometimes is possible to reconstruct the trajectory of individual neurons through the white matter (e.g., ref. 17). Given the inherent coarseness of DWI tractography, it can be argued that the prospect of using this method to reconstruct complex axonal pathways accurately in the human brain, in a manner similar to that used for molecular tracers in animals, is likely to be intrinsically problematic. Indeed, the limitations of DWI tractography techniques have been noted since their inception (8), and the anatomical accuracy of results from tractography based on the tensor model has been shown to be mixed (18). This inaccuracy has been attributed to two main factors. The first relates to the assumptions underlying tractography algorithms. For example, it has long been recognized that a simple tensor model (19) of local diffusion leads to problems in certain white matter regions where fibers cross within individual voxels. As a remedy, high angular resolution diffusion imaging (HARDI) methods (e.g., refs. 20–24) have been developed to enable better characterization of the diffusion displacement profile and to improve the accuracy of tractography. The second factor limiting accuracy stems from the low quality of clinical DWI data because of various sources of noise. Eddy current distortions, subject motion, physiological noise (see ref. 25 for a review), and susceptibility artifacts from echo planar imaging (EPI) (26) all lead to poor local characterization of diffusion and, consequently, to incorrect tractography results. Continuing advances in sequence design, MRI gradient hardware, and postprocessing correction schemes have overcome many of the initial problems (27) and have led to the belief that further acquisition improvements will result in more precise mapping of structural connections in the human brain (28). In fact, the assumption underlying many recent initiatives to map structural brain connectivity from DWI data is that improved image data quality and sophisticated diffusion modeling approaches will result in anatomically accurate maps of white matter connections (29). The goal of the present study is to investigate the validity of this assumption.To achieve this goal, we acquired high angular resolution DWI data from a normal adult rhesus macaque brain, ex vivo, at a spatial resolution of 250 microns (isotropic). This dataset is ideal for exploring the limits of DWI tractography because of its high signal-to-noise ratio (SNR) (for SNR computation, see SI Materials and Methods) and the almost complete absence of experimental confounds and artifacts such as those originating from patient motion, noise, cardiac pulsation, and EPI distortion that are typically encountered in in vivo studies. Using the axonal tracer results from a well-known atlas (17) as reference, we measured the sensitivity (i.e., the ability to detect true connections) and specificity (i.e., the ability to avoid false connections) of several DWI tractography implementations representative of the current state of the art. This approach allowed us to investigate whether sophisticated diffusion modeling techniques, when applied to DWI data of exceptional quality, would yield accurate maps of axonal connections.     

Depression in patients receiving pharmacotherapy for epilepsy: An audit in a tertiary care centre

BackgroundThe association of depression and epilepsy is thought to be bidirectional. The present study aimed to evaluate the prevalence of depression in patients on antiepileptic drugs (AEDs) and factors affecting it.MethodsIn this preliminary cross sectional study, patients at epilepsy clinic of a tertiary care centre were studied for occurrence of depression, using Hospital Anxiety and Depression Scale (HADS-D) and Patient Health Questionnaire (PHQ-2) scales. Correlation analysis was carried out to determine the factors associated with presence of depression in these patients.ResultsA total of 12 AEDs (maximum 5 per patient including older and newer) were prescribed to 933 patients in different treatment regimens over a period of 3 years. The median age of the patients was 22 years (10–77) and among them 63.5% were men. Mild and clinically relevant depression occurred in 279 (29.9%) and 223 (23.9%) patients, respectively. Mean HADS-D and PHQ-2 score was significantly higher with polytherapy as compared to monotherapy (p < 0.001). Patients on levetiracetam exhibited significantly higher HADS-D score in comparison to phenytoin (p < 0.001), carbamazepine (p < 0.001) and sodium valproate (p < 0.05). However, there was no significant difference in PHQ score among patients on monotherapy of different AEDs. Multivariate regression analysis suggested correlation between depression and seizure frequency, total number of AEDs and their load (p < 0.001).ConclusionDepressive symptoms were found to be present in more than half of the patients with epilepsy which require detailed work up for depression. Levetiracetam was found to be associated with a higher incidence of subclinical depression which needs further investigation.     

A template free protocol for fabrication of a Ni(ii)-loaded magnetically separable nanoreactor scaffold for confined synthesis of unsymmetrical diaryl sulfides in water

In the present report, an environmentally benign magnetically recoverable nickel(ii)-based nanoreactor as a heterogeneous catalyst has been developed via a template free approach. The catalytic performance of the synthesized catalyst is assessed in the confined oxidative coupling of arenethiols with arylhydrazines to form unsymmetrical diaryl sulfides under aerobic conditions. The salient features of our protocol include oxidant- and ligand-free conditions, use of water as a green solvent, room temperature and formation of nitrogen and water as the only by-products. Moreover, a broad range of functional groups are tolerated well and provide the corresponding diaryl sulfides in moderate to good yields. Moreover, the heterogeneous nature of the catalyst permits facile magnetic recovery and reusability for up to seven runs, making the present protocol highly desirable from industrial and environmental standpoints.

An environmentally benign nickel(ii)-based magnetic nanoreactor has been developed for oxidative coupling of arenethiols with arylhydrazines to form unsymmetrical diaryl sulfides in water at room temperature.     

Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome

The impact of glucocorticoids (GC) on skeletal development has not been established. The objective of this study was to examine changes in volumetric bone mineral density (vBMD) and cortical structure over 1 year in childhood nephrotic syndrome (NS) and to identify associations with concurrent GC exposure and growth. Fifty‐six NS participants, aged 5 to 21 years, were enrolled a median of 4.3 (0.5 to 8.1) years after diagnosis. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained at enrollment and 6 and 12 months later. Sex, race, and age‐specific Z‐scores were generated for trabecular vBMD (TrabBMD‐Z), cortical vBMD (CortBMD‐Z), and cortical area (CortArea‐Z) based on >650 reference participants. CortArea‐Z was further adjusted for tibia length‐for‐age Z‐score. Quasi‐least squares regression was used to identify determinants of changes in pQCT Z‐scores. At enrollment, mean TrabBMD‐Z (?0.54 ± 1.32) was significantly lower (p = 0.0001) and CortBMD‐Z (0.73 ± 1.16, p < 0.0001) and CortArea‐Z (0.27 ± 0.91, p = 0.03) significantly greater in NS versus reference participants, as previously described. Forty‐eight (86%) participants were treated with GC over the study interval (median dose 0.29 mg/kg/day). On average, TrabBMD‐Z and CortBMD‐Z did not change significantly over the study interval; however, CortArea‐Z decreased (p = 0.003). Greater GC dose (p < 0.001), lesser increases in tibia length (p < 0.001), and lesser increases in CortArea‐Z (p = 0.003) were independently associated with greater increases in CortBMD‐Z. Greater increases in tibia length were associated with greater declines in CortArea‐Z (p < 0.01); this association was absent in reference participants (interaction p < 0.02). In conclusion, GC therapy was associated with increases in CortBMD‐Z, potentially related to suppressed bone formation and greater secondary mineralization. Conversely, greater growth and expansion of CortArea‐Z (ie, new bone formation) were associated with declines in CortBMD‐Z. Greater linear growth was associated with impaired expansion of cortical area in NS. Studies are needed to determine the fracture implications of these findings. © 2013 American Society for Bone and Mineral Research.