We prospectively and longitudinally assessed regional and global changes in gray and white matter volumes in patients with TAI scanned acutely and again several months after injury using FreeSurfer morphometry, while also investigating the relationship between atrophy and functional outcome. The distribution of atrophy was essentially symmetric. Substantial atrophy was observed in the cerebral cortex, subcortical structures, and white matter. Loss of WBPV was predictive of poor outcome, as was atrophy in several brain regions. This represents the first application of FreeSurfer morphometry in a longitudinal investigation of adult TBI.
Our findings of significant decreases in global brain volume after traumatic insult are consistent with previous studies. In a recent longitudinal study of 24 patients with severe TBI, brain parenchymal volume decreased by a mean of 4.0% between initial MRI at 8 weeks and follow-up MRI at 12 months.10
Another longitudinal study of TBI patients with injuries ranging from mild to severe found a mean decrease in brain parenchymal volume of 1.43% between 11 weeks and 13 months post-injury.16
Lastly, a smaller study of patients with mild and moderate TBI found a mean decrease in brain volume of 4.16% over any interval of at least 3 months, however the time to initial MRI varied from 7 to 430 days after trauma.6
The loss of WBPV in our study (mean 4.5%) is higher than in prior studies. This is likely the consequence of obtaining the initial MRI earlier (median 1 day), therefore increasing our ability to detect atrophy in the acute and early subacute post-traumatic period. As noted previously, it is probable that the rate and distribution of atrophy are dependent on time after injury,10
and higher atrophy rates may occur during the acute/early subacute period than during the late subacute/chronic period. In addition, differences in global atrophy rates may be related to the automated methods used for morphometric analysis, which may result in minor variations in calculation of WBPV.25
Our study examined patients whose predominant injury mechanism was TAI, excluding those with focal lesions > 10 ml and those requiring cranial surgery. Even in the absence of focal trauma, there was substantial loss of brain volume, supporting the hypothesis that a primary mechanism of post-traumatic atrophy is diffuse white matter damage with secondary Wallerian degeneration and eventual neuronal cell death. A previous study from our group examined the relationship between acute measures of white matter integrity and global atrophy in patients with TAI, finding that acute axonal lesions (within 1 month of injury) measured by fluid attenuation inversion recovery (FLAIR) imaging were strongly predictive of atrophy at 6 months.9
A recent study of patients with severe TBI, not limited to those with TAI, found the most substantial decreases in brain volume in regions susceptible to the consequences of TAI.10
However, since conventional neuroimaging techniques including CT and structural MRI have low sensitivity for TAI, it is likely that patients with focal hematomas also had significant diffuse axonal injuries, potentially explaining the similarities between our findings and previous work.6,10,16
In order to improve post-traumatic outcomes, it will be essential to advance clinical detection and diagnosis of TAI.
Post-traumatic atrophy was not uniformly diffuse. Amongst subcortical structures, the highest rates of atrophy were noted bilaterally in the amygdala, hippocampus, thalamus, and putamen. Atrophy in the thalamus and putamen have been observed in several previous TBI studies.13,14,26
Loss of volume in the amygdala and hippocampus may contribute to various behavioral and cognitive difficulties that commonly affect head-injured patients such as lability of mood, heightened irritability, and difficulties with memory and learning.
In cortical analysis, a variety of regions experienced marked atrophy, with the most dramatic volume loss occurring in the parietal lobes, superior frontal lobes, precuneus, and paracentral lobules. A recent longitudinal study found decreased volume in the supplementary motor area and pre- and post-central gyri,14
while another found atrophy only in small portions of the frontal cortex.10
The apparent disparity in degree of cortical atrophy in our study versus previous studies is likely due to inter-subject variability in cortical sulci and gyri that make volumetric analysis of the cortex exceptionally difficult with traditional voxel-wise approaches. The application of FreeSurfer
morphometry to this study improves the ability to delineate and quantify the cerebral cortex at the subvoxel level, resulting in increased sensitivity for cortical volume loss. In addition, previous studies have not excluded patients with focal lesions that may further obscure cortical morphometry. Although extensive, cortical atrophy was not diffuse, and several regions, including the entorhinal cortex, parahippocampal gyrus, and fusiform gyrus, were resilient to atrophy. Larger studies with increased follow-up times will be needed to improve the detection and quantification of regional volume changes after TAI.
Regionally selective cortical and subcortical atrophy has been studied extensively in Alzheimer’s disease, and we note that many of the areas that are particularly susceptible to atrophy in Alzheimer’s disease are also vulnerable after TAI. For example, in addition to hippocampal volume loss, patients with Alzheimer’s disease have high rates of atrophy in the amygdala,27-29
precuneus, parietal, and frontal cortex,30-32
and corpus callosum.33-36
While interesting, the relationship is far from perfect, and some regions that undergo substantial atrophy in Alzheimer’s disease, such as the medial-inferior temporal lobe, may be relatively preserved after TAI. However, it is plausible that regional similarities in atrophy between TAI and Alzheimer’s disease may contribute to post-traumatic deficits in certain cognitive domains such as learning and memory. We also note that many brain regions vulnerable to atrophy in our study and in Alzheimer’s disease are involved in the default network.32
These findings may relate to common molecular mechanisms shared between Alzheimer’s disease and TBI-related neurodegeneration.
As expected, loss of WBPV was predictive of disability at time of patient follow-up, with a nearly 30-fold increase in disability risk in patients with 10% atrophy. In addition, volume loss in several candidate brain regions displayed prognostic value for outcome, suggesting that regional morphometry may hold value as a biomarker for recovery after trauma. While interesting, our analysis involved only a small number of patients and was by no means exhaustive. In order to better understand the influence of regional volume changes on patient outcomes, it will be necessary to assess atrophy-outcome relationships for a greater number of brain regions in a larger number of patients with more precise metrics of functional recovery after brain trauma such as neuropsychological battery tests.
There are several limitations to our study. We assessed longitudinal changes in brain volumes between the acute and late subacute time periods. As the brain may swell acutely after injury, it is possible that the clearing of brain edema may contribute to observed losses of brain volume. However, in cross-sectional comparisons between control and acute patient scans, there were no significant differences in cortical or subcortical brain volumes. The only significant difference between groups was volume of the lateral ventricles, which were larger in controls, suggesting that there may be diffuse swelling after injury. However, as ventricular enlargement is at best an indirect measurement of atrophy, it is much less sensitive than direct measurement of changes in structural volumes.13
Therefore, it is unlikely that brain edema played a substantial role in observed decreases in brain volume. This study contained only a modest sample size, and in order to further our understanding of atrophy after TAI, it will be necessary to enroll a larger number of patients. In addition, follow-up MRI scans were not performed on controls, which would have permitted more robust comparisons between independent groups. Controls and patients were matched based on gender and age, but not on years of education. This resulted in a control group with a significantly higher education level, which could potentially confound between-group comparisons. Finally, this longitudinal study utilized two time points for quantitative MRI, and only assessed atrophy that occurred between the acute and late subacute time periods. In order to more fully understand the time course and regional distribution of post-traumatic atrophy, it will be necessary to obtain additional serial MRI scans at shorter time intervals and over a longer study time period.
This prospective evaluation of longitudinal changes in brain volumes after TAI offers new information on the spatial distribution of post-traumatic cerebral atrophy. Our findings indicate that atrophy is not uniformly diffuse, but rather has substantial selectivity for various subcortical and cortical regions including the amygdala, hippocampus, thalamus, precuneus, parietal, and frontal cortex. Atrophy in several brain regions may be also be predictive of long-term functional recovery. Future studies will be needed to determine the impact of regional atrophy on particular neuropsychological outcomes. Finally, it will be necessary to integrate regional volumetric data with measurements of axonal integrity in order to assess the true relationship between acute white matter injury and chronic volume loss in corresponding gray matter.