An arbitrary starting point must be selected, whose exact location, size and orientation significantly affects results. Tractography algorithms differ in detail between vendors and arbitrary decisions must be made as to when tracking should stop. The ethics board of the institution approved this study, which followed the tenets of the Declaration of Helsinki, and all participants provided informed written consent prior to their participation. All patients and control subjects underwent repeat neuro-ophthamic testing, which included best-corrected high-contrast letter acuity using Early Treatment Diabetic Retinopathy Study charts at 3.
The right eye was tested first, followed by the left eye. Visual acuity scores were recorded as the 4-m logarithm of the minimum angle of resolution logMAR , where each 0. Slit lamp biomicroscopy and dilated ophthalmoscopy were also performed at each visit. Twenty-one patients returned for a follow-up session approximately 6 months later mean, 5.
Control subjects underwent one MRI session. These individuals were recruited throughout the entire study period. Foam padding was used to minimize head movements, and participants were instructed to lie still and close their eyes. Sagittal anatomical images were collected first to identify the optic nerve. An iterative nonlinear shimming sequence GE Healthcare was used to minimize the heterogeneity of the magnetic field around the optic nerves.
Prior to image reconstruction, DTI images were zero-padded such that the resulting resolution was 0. Whole-head T 2 -weighted imaging was performed to visually inspect the afferent visual pathway for the presence of sclerotic lesions. All image processing was performed without any knowledge of patient clinical characteristics or disease status. An example is shown in Figure 1. This method has been shown previously to possess good intra- and interrater reliability for accurate segmentation of the optic nerve.
Figure 1. View Original Download Slide. T 2 -weighted b 0 images of the optic nerves. The images are perpendicular cross-sectional images through the optic nerves. Images to the left show the original images, and the images to the right show the optic nerve segmentation. Red indicates segmented right optic nerve, and green indicates segmented left optic nerve. Figure 1 T 2 -weighted b 0 images of the optic nerves. For each DTI measurement and each eye, the mean and coefficient of skewness from acute ON patients were each compared with controls using an independent samples t -test.
This analysis was also applied to data collected at 6 months. For data collected during acute ON, a Spearman rank correlation analyses was performed between visual acuity of the ON eye and each of the mean and the coefficient of skewness of each DTI measurement.
For both the mean and the coefficient of skewness, a paired samples t -test was used to compare ON eyes with fellow eyes. Paired samples t -tests were performed again for data collected at 6 months. All statistical tests were corrected for multiple comparisons using the family-wise error rate.
From the first imaging session, the data of three ON patients were excluded due to excessive head motion during scanning, leaving data from 21 patients for analysis. The data from one ON patient were excluded from the 6-month scanning session, leaving data from 20 patients for analysis.
As a result, 17 patients had data from both imaging sessions. All control participant data sets were analyzed. Patient demographics and clinical characteristics are summarized in the Table. During acute ON, patients exhibited reduced visual acuity of the ON eye, which as a group, improved to normal by 6 months Table. All control subjects exhibited normal visual acuity. Visual inspection of T 2 -weighted images did not reveal any discernible lesions along the afferent visual pathway in any of our patients.
Table View Table. Participant Characteristics. Table Participant Characteristics. Interrater reproducibility of optic nerve segmentation was high. The mean difference between raters in the voxels deemed to be in the optic nerve was 9.
As a result, the difference in FA between raters was 1. This is in good agreement with past studies using manual segmentation of the optic nerve in DTI images. There were no differences in DTI measures between fellow eyes and controls eyes acutely or after at 6 months. No significant differences were observed for mean FA in any of these comparisons. There was no trend for an association between visual acuity and FA in ON eyes. Figure 2. Diffusion measurements for patients ON and fellow eyes and controls.
No significant differences were observed for mean FA. For example, in the case of brain tissue, water molecules diffuse more freely along the axon but are relatively constrained from escaping it or moving across the walls of axons.
This coherent directionality is therefore called anisotropic. By calculating the diffusivity along multiple directions, the diffusion tensor may be calculated and it becomes possible to estimate the orientation of axon bundles Mori, This assumption that anisotropy in white matter is caused by cellular structures delimiting free water diffusion is reasonable at face value. Thus, the axon itself a tubular, relatively rigid structure may be sufficient to generate anisotropy in white matter.
Additional limitations to molecular motion come from myelination, as multiple myelin sheets create a compact lipidic cover that isolates the axon. Thus, although myelination contributes to FA, other sources, including the axon itself, seem to provide the greatest FA. Additionally, it is unknown whether barriers or intermolecular binding affect the water diffusion within the axon, but it is logical to assume so.
In spite of the uneven contributions of axon and myelin to anisotropy, changes to each of these structures cannot be distinguished on the basis of diffusion tensor imaging DTI results.
To illustrate, a recent investigation in animal models of multiple sclerosis compared mice treated with the drug cuprizone, which produces inflammation and demyelination without damaging the axons themselves, against mice treated with a combination of cuprizone and a peptide which leads to demyelination as well as axonal damage.
Perhaps unsurprisingly, the results revealed that FA values cannot distinguish between the demyelination group and the demyelination plus axonal damage group Boretius et al. Combination of DTI with histological techniques may facilitate the interpretation of underlying pathology in white matter diseases. Thus, although diffusion anisotropy theoretically reflects microscopic anatomy, spatial resolution obtained by MR-DTI remains at the macroscopic level a typical voxel size is around 2 by 3 mm.
Consequently, discrepancies between levels, that is, the microscopic level which underlies anisotropy and the macroscopic level observed with this technique, are to be expected and inferences regarding the former on the basis of the latter should be made with caution. A particularly challenging illustration is the identification of crossing fibers. In this situation, a single voxel may be composed by fiber populations with different spatial orientation resulting in an average increase in FA, which in such a case would not be due to changes in axonal or myelin structure.
For the previously exposed reasons, FA is not always a reliable marker of white matter integrity and convergent findings from different techniques should be used to interpret the results. Indeed, an alternative method has recently been developed that may overcome some of the limitations of FA analysis. The new method models the effect of spin motion on the MRI signal to extract information about the microstructure from the motion of the spins, allowing to represents the motion properties in an asymmetric, unconstrained, unrestricted fashion Ozcan, This approach may shed new light on the changes at the intersection of crossing fibers pathways and within isosurfaces of gray matter Ozcan, White matter abnormalities have been proposed to be central to the pathophysiology of schizophrenia Haroutunian and Davis, ; Takahashi et al.
Recent evidence suggests that dysfunction in myelination and altered oligodendrocytes OLG number and function may contribute to schizophrenia Flynn et al.
The latter study revealed that N-acetylaspartarte, a source of acetyl groups which are incorporated into myelin, is deregulated in schizophrenia possibly underlying reductions in white mater volume. Focus on altered central nervous system myelination in schizophrenia has led to a number of studies implicating oligodendrocyte dysfunction Uranova et al.
For example, mRNA expression of four oligodendrocyte related genes with variants associated with schizophrenia found that although expression was not reduced, patients carrying risk alleles had lower transcript levels Mitkus et al. Likewise, expression of a variety of oligodendrocyte genes has been found to be altered particularly the temporal lobe Katsel et al. Oligodendrocyte pathology seems to be closely related to MRI-detected white matter abnormalities in schizophrenia Segal et al.
Several recent studies attempt to directly demonstrate a link between genetic variation and white matter integrity Braskie et al. Thus, a single nucleotide polymorphism rs in the gene for the transcription factor OLIG2 necessary for oligodendrocyte generation has an allele associated with reduced white matter integrity, measured with FA, in the corona radiata bilaterally in healthy volunteers Prata et al.
Notably, genetic variation within the OLIG2 gene including the allele just referenced is associated with schizophrenia in at least two samples Georgieva et al.
Similarly, genetic variation in the NTRK1 gene, which is associated with nervous system development and myelination, also predicts FA in healthy volunteers Braskie et al. Interestingly, diffusion perpendicular to the axon fiber but not diffusion parallel to the fiber was directly correlated to FA in this sample.
Such finding has implications for the molecular underpinning of the DTI measure, as diffusion perpendicular to the axonal tracts is thought to reflect lack of myelin and increased permeability instead diffusivity parallel to the axonal tracts may reflect axonal integrity Song et al. Again this finding is in line with investigations showing an association between variation in NTRK1 and genetic risk for schizophrenia van Schijndel et al.
Further studies linking genetic variations in schizophrenia with white matter abnormalities are anticipated. In the preceding paragraphs we have discussed data suggesting dysfunction of white matter components and in diffusion weighted MRI in schizophrenia without a particular attention to specific white matter tracts. In general, FA is globally decreased Douaud et al. Also, although low FA is usually associated to poor cognitive performance in healthy as well as in some clinical populations Turken et al.
Since an exhaustive review of the white matter changes in schizophrenia is beyond the scope of this paper, over the next few paragraphs we will focus on those changes that have been shown to correlate specifically with models of symptom generation which may help understand the relationship between anisotropy and functional changes.
We will pay particular attention in our comments to studies of subcortical white matter Table 1 which have not been specifically discussed in currently published reviews even though several original publications have become available see below. Table 1. Fractional anisotropy in subcortical white matter of subjects with schizophrenia. Schizophrenia is reportedly associated with reduced FA in frontal regions, which correlates with cognitive and motor deficits in patients Walther et al.
In addition, better performance on attention and executive function tasks was associated with higher levels of FA in task-relevant regions in subjects with schizophrenia Lim et al.
But contrary to the excessively simplistic postulate that more FA is always better, patients who hear conversing hallucinations have increased FA in interhemispheric auditory fibers compared to patients without this symptom or, to a lesser extent, to healthy controls Mulert et al. Moreover, higher FA in fibers connecting temporal regions such as the arcuate fasciculus or the superior longitudinal fasciculus was found to be associated with increased severity of hallucinations in schizophrenia patients Hubl et al.
The arcuate fasciculus connects the posterior temporal gyrus with the inferior frontal gyrus which underlies speech and vocal processing. Increased FA in the arcuate fasciculus bilaterally is likely to contribute to the pathophysiology underlying hallucinations in schizophrenia Alba-Ferrara et al.
As a result of such changes, persons with schizophrenia would misidentify self-generated auditory objects as coming from external sources Mechelli et al. Alternatively, but not necessarily in contradiction, diffusion abnormalities may decrease speed of axonal transmission speed resulting in neural timing abnormalities.
Indeed, schizophrenia patients experience time-delayed corollary discharges to self-generated auditory stimuli, resulting in aberrant suppression of the sensory consequences of self-generated actions Whitford et al. Thus, schizophrenia patients have a combination of increased and decreased structural and functional connectivity in specific brain networks, and it is likely that different clinical profiles may explain differences in the reported findings on DTI studies.
Although a vast majority of DTI studies in schizophrenia have focused in the white matter tracts connecting between cortical structures, subcortical structures have recently started to draw the focus of attention. Eight were right-handed. DTI metrics from the roots are shown in Table 1.
There was significant variability between subjects DTI metrics Table 2. The mean MD varied by a mean of 0. The mean AD varied by a mean of 0. The RD varied by a mean of 0. The FA was statistically higher on the right side, although the absolute difference was very small mean difference 0.
Similarly, the FA was statistically higher in the roots of the dominant limb mean difference 0. There was no statistically significant difference in the FA measurements from the roots of men and women mean difference 0.
The MD was statistically higher on the right side mean increase 0. There was no statistically significant difference in the MD of the roots between men and women mean difference 0.
The AD was statistically higher on the right side mean increase 0. Again, there was no statistically significant difference in the AD of the roots between men and women mean difference 0. There was no statistically significant difference in the RD between the right and left side mean difference 0. Overall, at higher FA thresholds fewer tracts were propagated Fig. There was no statistically significant difference in the proportion of tracts rendered at FA thresholds of 0.
In comparison, thresholding the FA at 0. This appears to be due to partial volume effects reduce by cerebrospinal fluid as the FA in the rootlets is substantially lower than the spinal cord and extraforaminal portions of the spinal roots Figs.
Overall, the FA threshold was strongly associated with tract length Fig. Using a FA threshold of 0. This work helps to define the FA thresholds needed for tractography of the roots of the brachial plexus in healthy adults. This information may be used to inform decisions regarding tractography conditions in future studies of the brachial plexus in adults.
We have shown that the DTI metrics and FA thresholds for tractography of the brachial plexus appear to be different to the white matter tracts in the brain. Lebel and colleagues 18 showed that the mean FA of white matter tracts in the adult brain is 0.
However, we have shown that the extraforaminal roots have a lower mean FA. Whilst the brachial plexus roots are akin to white central matter tracts in that they are myelinated and highly ordered , the fascicular arrangement in the roots is substantially different in two main ways:.
The density of axons per mm 2 in the roots of the brachial plexus is 5 times less than the genu of the corpus callosum 19 and half that of the pyramidal tracts of the spinal cord Compared to the central nervous system, the fourfold lower density of axons per mm 2 partly explains the lower FA.
Unlike the central white matter tracts, axons and fascicles in the roots bifurcate, merge, weave and exchange throughout the brachial plexus from the level of the intradural rootlets to the target organ These intraneural and interfascicular connections will increase signal dispersion and may further explain why the FA is lower in the roots of the brachial plexus than in central white matter tracts.
Although our findings are in agreement with the metrics reported in many DTI studies of the brachial plexus 4 , 5 , 6 , 7 , 9 , 10 , 26 Supplementary Table 2 , our FA values are slightly lower. FA is a function of numerous factors such as the b-value and number of diffusion encoding directions 27 , Therefore, it is plausible that other studies of all which use smaller b-values and fewer directions may be reporting upwardly biased estimates of the FA which underestimate dispersion 29 , Future studies should consider acquiring data from higher b-values which are sensitive to restricted diffusion and explore how different models such as NODDI or model-free methods such as generalised q-space imaging effect the diffusion metrics.
As with different regions of the brain, the ideal tractography conditions for peripheral nerves differ from region-to-region. Therefore, it is important that researchers and clinicians have evidence on which to base their selection of brachial plexus tracking thresholds so as to propagate tracts which represent real connections and equally, avoid propagating false tracts, e.
Similar studies of FA thresholding in the brain have shown that it has considerable effect on the number, density and directionality of tracts, as well as tract-based estimates of anisotropy and diffusivity 32 , 33 , Therefore, we argue that using a FA threshold generalised from tractography studies in the brain or elsewhere is inappropriate.
Similarly, DTI provides reconstructions which are closest to the ground truth, with the greatest valid:non-valid connection ratio However, the prevalence of false connections remains high and the utility of tractograms still remains unclear Whilst we used topology-informed pruning 17 to remove false tracts, this technology has not be validated in peripheral nerves.
Equally, we have shown that altering the FA threshold affects tract length, with some tracts potentially being falsely propagated or inappropriately long. Therefore, our findings should be interpreted with caution and we recognise the need for further studies examining the association between tractograms generated under different conditions and the ground truth of anatomical dissections.
The literature is lacking reliable research concerning DTI metrics in human peripheral nerves in health, after injury or disease onset, and how these relate to nerve degeneration and regeneration. Until these fundamental questions are answered, the translational value of our work can only be speculated. Equally, this study considers data from the first 5—7 cm of the brachial plexus and our findings should not be extrapolated beyond this anatomical area. We advocate the development of a biobank for diffusion MRI of peripheral nerves; ideally this would contain data from healthy adults, recently deceased donors and fixed cadavers to permit comprehensive analysis of the effects of numerous co-variables on DTI metrics throughout the length of the nerves.
Future work should compare different software for artefact correction and approaches forward full dataset with reversed b0s vs. Our sample is small and originates from a single scanner within one centre, which may limit the generalisability. In an effort to reduce scan time and thus, the opportunity to scan more people to generate estimates of normality, our future work will explore different q-space sampling strategies, signal averaging, multiband simultaneous multislice imaging and pre-processing pipelines.
We observed differences in the FA and MD of right versus left sided roots, which was independent of handedness. This is difficult to explain biologically, so may represent: a type 1 errors, b a insufficient data from left-handed individuals which might translate to less precise estimates of the variance, c idiosyncrasy related to the study design or sample, d field inhomogeneities or otherwise.
Further work and ideally an individual participant data meta-analysis, using data from a biobank could investigate how DTI metrics from each root differ in the dominant versus non-dominant limb. The fractional anisotropy threshold required to generate tractograms of the roots of the brachial plexus appears to be lower than those used in the white matter pathways in the brain. We provide estimates of the probability of generating true tracts for each spinal nerve root of the brachial plexus, at different fractional anisotropy thresholds and show how this affects tract-related metrics.
Wade, R. MRI for detecting root avulsions in traumatic adult brachial plexus injuries: a systematic review and meta-analysis of diagnostic accuracy.
Radiology , — Article Google Scholar. Heckel, A. Peripheral nerve diffusion tensor imaging: assessment of axon and myelin sheath integrity.
Vargas, M. Diffusion tensor imaging DTI and tractography of the brachial plexus: feasibility and initial experience in neoplastic conditions. Neuroradiology 52 , — Tagliafico, A. Brachial plexus MR imaging: accuracy and reproducibility of DTI-derived measurements and fibre tractography at 3. Oudeman, J. Diffusion tensor MRI of the healthy brachial plexus.
0コメント