To the best of our knowledge, this is the first meta-analysis of DTI studies of mTBI patients to demonstrate significantly reduced FA and significantly increased MD in the CC compared with controls, without publication bias and with no heterogeneity. In addition, a subanalysis based on the subregions of the CC demonstrated a significant decrease of FA and significant increase of MD in the splenium, a marginal reduction of FA in the midbody and no changes in FA and MD in the genu of the CC. The viability of the FA reduction and increase in MD in the whole CC and splenium were examined by a one-way sensitivity analysis of each meta-analysis. Sensitivity analyses further demonstrated that these findings were preserved in specified subgroups with studies without psychiatric disorders.
Of the types of DTI studies, the hypothesis-free, whole brain analyses, such as VBA or TBSS approaches are useful to investigate the overall changes in white matter, rather than specific white matter tracts or areas.13
In contrast, the other type of DTI study, the ROI analysis, which investigates a priori-defined region or tractography, is useful to investigate specific tracts and defined ROI, and report invariances derived from tensor imaging. Thus, selecting DTI studies with a priori-defined design analysis is rational when we have an a priori hypothesis that DTI in the CC may be the potential tool to detect microstructure damage in the white matter following mTBI.
The significant FA reduction demonstrated by our meta-analysis suggests the potential diagnostic ability of DTI in mTBI patients. Our findings have provoked the assumption that previous studies were unable to demonstrate significant differences because of the small number of participants and varying duration after trauma.
In keeping with the findings of a previous study that reported unmyelinated axons in the CC after animal TBI,48
we found that a reduced FA value indicates differences in cellular membrane integrity, fiber myelination, fiber diameter and directionality in the CC after mTBI. The CC is the main fiber tract that connects the hemispheres and is topographically organised. The genu of the CC represent fibers from the prefrontal cortex; the midbody is composed of fibers from the premotor, motor, parietal and superior temporal cortex; and the splenium represents fibers from the inferior temporal and occipital cortex. There are some possible reasons why the CC is vulnerable to mTBI. First, the CC is a very organised area of the brain, with axons predominantly oriented in one direction, is inherently anisotropic and has higher FA values compared with less organised areas of white matter. Second, as the CC connects both hemispheres, external accelerational forces at a lateral or oblique-lateral angle of rotation can cause injury to the CC.49
In addition, the CC has been recognised as a region frequently injured by shear strain,50
as shown in victims of shaken baby syndrome.51
The meta-analysis clearly demonstrated selective FA reduction in the posterior part of the CC, such as it reached significance in the splenium and a marginal difference in the midbody, as well as selective MD increases in the splenium. MD is another invariant that is often reported in DTI studies, which is a measure of the average molecular diffusion independent of any tissue directionality and is affected by cellular size and integrity.1
Results, such as lower FA and higher MD, imply that the posterior part of the CC is more vulnerable to injury than the anterior part like the genu. The vulnerability of the posterior part of the CC compared with the anterior part has been repeatedly reported by imaging studies of brain injury.50
One MRI study reported that 80% of CC injury was distributed in the posterior part in patients with a moderate to severe TBI.55
Though the mean age of the included studies was limited, ranging from 27 to 42, it had a marginally significant effect on the FA reduction in the splenium (p=0.06). Although we are unable to offer a compelling explanation for this relationship, it may potentially be due to age-related changes in white matter maturity. Previous studies have reported that FA is increased during childhood and adolescence, and reaches its peak value at around age 30, then gradually decreases.56
An external trauma may accelerate the loss of FA. To test this relationship, a large-scale original study is required.
There are a number of clinical and methodological confounds that may effect the result. For example, sexual dimorphism of the CC in DTI has been reported.57
Although meta-regression showed no significant relation between male ratio and effect size, male ratio was not available from all the studies. Thus, the finding should be interpreted with caution. Medication and substance misuse also influence results.58
Though no studies reported participants of substance misuse, some studies did not clarify that they excluded individuals with substance abuse, and sensitivity analysis excluding them did not show significant difference. Thus, the potential effect of medication or substance abuse is not completely assessed. With regard to strength of magnetic field, although sensitivity analysis with studies which utilised a 1.5-T scanner preserved the findings, sensitivity analysis with a 3-T scanner did not show significance. As microstructure damage is more detectable in stronger magnetic field, this result is against the hypothesis.
Our study, however, does have several methodological considerations and limitations that must be acknowledged. Due to the nature of a meta-analysis, we can make statistical analysis only at the level of studies, with no way of confirming that the mTBI participants of the included studies actually exhibited the findings presented. We found considerable heterogeneity between studies that may attribute to methodological issues. Some of the included studies utilised a 1.5-T MR scanner, while others used a 3-T. In addition, the NEX, b factor and number of directions are considerably different. Although we employed a random effect model to tolerate heterogeneity, the different methodologies integrated from these studies may be criticised. Although we conducted a comprehensive literature search and meta-analyses of the CC, IC and corona radiate, there is the possibility that other brain areas could also present white matter changes that were not investigated in this meta-analysis.59
In addition, we cannot deny the probable existence of the data we could not find. Further, though we have demonstrated significant FA reductions in the CC of mTBI patients with a large effect size, the large total number of participants could help the small differences reach significance. Additionally, it has been repeatedly reported that mTBI patients were at risk of developing mental health problems, such as depression and substance misuse, versus those mental health problems that are common among individuals who have mTBI.60
And it is widely known that those mental health problems alter DTI values.61
Although sensitivity analysis with studies without major psychiatric disorders preserved the significance of the findings, due to lack of sufficient number of studies that investigated mental health problems among mTBI patients, it was impossible to examine whether the DTI change demonstrated any result from pure injury or was related to psychological problems that may be the cause and sequel of injury.
Finally, it is a pivotal point that diagnostic tools of mTBI are changing. Almost all the included studies recruited patients with a GCS scored between 13 and 15, however, there has been a recent argument on the definition of mTBI, and whether it should include patients with a GCS score of 13.62