Table 1. . Publications on white matter changes in human mild traumatic brain injury since 2011.
| Number of subjects | Age (years)/(F/M) | Postinjury time | Field strength (T) | Technique/analysis method | Affected/measured WM regions | Major conclusions | Ref. |
|---|---|---|---|---|---|---|---|
| m: 23 (11 [GO]/12 [PO]) C: 23 |
C:30 ± 8.4 (11/12); GO: 27.8 ± 8.5 (3/8) PO: 31.3 ± 8.4 (5/7) |
Between 7 and 28 days and between 3 and 4 months | 1.5 | DTI/TBSS | Increased MD in CC, the right ATR and the SLF, the ILF and the FOF bilaterally | DTI at the subacute stage may be a predictive marker of poor outcome | [43] |
| m: 60 (with PCD: 21; without PCD: 39) C(OI): 32 |
Between 19 and 55 m: (17/43) OI: (9/25) |
6–8 weeks | 3 | DTI/ROI | MD of SCC | Does not support an association between WM integrity in the CC and self-reported PCS 6–8 weeks post mTBI | [44] |
| m: 25 (veterans exposed to BI) C: 33 |
BE: 24–55 No BE: 22–52 (4% females) |
2–5 years | 3 | DTI/Voxel-wise | Forceps major and minor, bilateral anterior thalamic radiations, right corticospinal tract, bilateral IFOF, bilateral ILF and left SLF | Blast mTBI disrupts integrity of number of white matter tracts; these disruptions are diluted by averaging across large number of voxels within an ROI; the neurological effects of blast mTBI are diffuse, widespread and spatially variable | [45] |
| m: 34 C: 30 |
m: 29.9 ± 6.4 (M); (19/15) 38.9 ± 13.2 (F); C: 36.6 ± 11.9 (M); 38.1 ± 10.3 (F) (14/16) |
<2 weeks, 3 and 6 months | 3 | DTI/enhanced Z-score micro-structural assessment for pathology (EZ-MAP; voxel-wise analysis) | High FA most frequently detected in the deep and subcortical white matter of the frontal, parietal and temporal lobes, and in the anterior portions of the CC Low FA values were observed in CR (anterior and superior), SCC, precentral white matter, IC and deep and subcortical WM | Unique spatial patterns of WM abnormalities in each patient Implications of high FA remain unclear, but may be evidence for a compensatory mechanism or plasticity in response to injury, rather than a direct manifestation of brain injury |
[7] |
| m: 8 C: 0 |
Between the ages of 18 and 40 (3/5) | <48 h | 3 | DTI/ROI based on tractography | Cingulum | Memory performance appeared to mirror changes in FA in certain cases, supporting a pathophysiological basis to memory impairment following mTBI | [46] |
| m: 5; C: 50 |
m: (37.1 ± 10.2) (33/28) C: (35.8 ± 13.4) (20/30) |
At least 6 months | 1.5 | DTI/TBSS | Right SLF, left superior frontal gyrus, right insula and left fornix | In the chronic stage certain regions have abnormally reduced WM integrity; these brain regions perhaps are related to chronic persistent cognitive impairments | [47] |
| m: 14 (4 with MDP and 10 without MDP) C: 0 |
MDP: 37 ± 9 (0/4) W/O D: 35.7 ± 12 (4/6) |
MRI within 1 month | 3 | WM abnormalities in the frontotemporal regions in the depressed group | Compared with the nondepressed group, those who developed depression had white matter abnormalities | [48] | |
| m: 46 (22 with LOC; 24 with AOC) C: 0 |
LOC: 29.1 ± 6.07 AOC: 26.5 ± 4.92 (0/46) |
Not indicated | 3 | DTI HARDI acquisition/TBSS analysis | FA is significantly lower in LOC compared with AOC in bilateral brainstem, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, body of the CC, cingulum, SLF and anterior thalamic radiations | Evidence of microstructural alterations in individuals with history of LOC, and may suggest brain basis for psychiatric symptoms and mental illness following mTBI | [49] |
| m: 14 C: 14 |
m: 34.9 ± 18.4 (5/9) C: 35.8 ± 18.5 (5/9) |
2 days (12–72 h) and 1 month (28–43 days) | 3 | DTI/TBSS | Anterior CC, right CR and IC | TBSS showed fractional anisotropy (FA) to be significantly lower, and mean diffusivity (MD) to be higher in the mTBI group in several white matter tracts (FA = 40,737; MD = 39,078 voxels) compared with controls at 72 h after injury and still 1 month later for FA. Results underscore the importance of strictly defined image acquisition time points when performing MRI studies on patients with mTBI | [50] |
| m: 26; C: 13 |
m: 30 ± 11(5/25) C: Not indicated |
3–55 days | 3 | MRS/Global | PCS-positive patients (n = 15) had lower WM NAA than the controls (n = 12) | Global WM NAA, showed sensitivity to the TBI sequelae associated with common PCS | [9] |
| m:20 (at base line) and 10 at follow-up; C: 16 |
m: 34.8 ± 10.7 (4/16 at baseline 2/8 at follow-up) C: 35.1 ± 11.9 (3/13) |
Within 1 month and >9 months | 3 | DTI and DKI/ROI | IC, EC, CC, cingulum, CSV at baseline. CC, cingulum, optic radiations and CSV at follow-up | DTI and DKI, I might be useful for investigating dynamic changes in WM and cognitive impairment during a short follow-up period | [51] |
| m: 11 with PPCS; C: 11 |
m: 32.1 ± 8.5 (2/9) C: 32.1 ± 8.5 years (1/10) |
62.08 ± 46.3 months | 3 | DTI/ROI | CC | Individualized analysis shows promise for enhancing clinical care of PPCS patients as it could play a role in the diagnosis of brain injury not revealed using conventional imaging | [52] |
| m: 11 C: 11 |
m: 15.09 ± 1.14 (6/5) C: 15.82 ± 1.78 (6/5) |
1–6 days | 3 | DTI/ROIs on fiber tracts | Fornix | Relation between lower performance on cognitive tasks and higher FA in fornix | [53] |
| m: 34 C: 42 |
m: 34.9 (not indicated) C: 38.3 (20/22) |
<2 weeks | 3 | DTI/Voxel wise analysis (FMRIB diffusion toolbox) | Multiple WM regions, depending on individual patient | EZ-Map was used to provide robust approach for detecting abnormal FA in individual patients | [54] |
| m: 34 (with blast) C: 18 (without blast) |
Blast: 31.6 ± 9.2 (0/34) nonblast: 32.8 ± 7.3 (1/17) |
Not indicated | 3 | DTI/Voxel-wise analysis MPF based on MTR | Reduced FA in right genu of the CC in blast vs nonblast veterans; lower MPF in right genu of the CC, capsule-anterior limb); the interlobar right SLF; frontal and parietal subgyral WM (i.e., right precentral, superior white matter hyperintense lesions on FLAIR sequence were observed in mTBI [32]. In veterans with mTBI, it was shown that these lesions have an effect on verbal memory, independent of the presence of PTSD and middle frontal gyri, medial parietal gyrus/precuneus and left superior parietal lobule); frontal GM/WM border regions (i.e., right superior and middle frontal and left inferior frontal gyri | Veterans with one or more blast-related mTBIs exhibit abnormalities of brain WM structural integrity and macromolecular organization that are not related to comorbid PTSD | [55] |
| m: 30 (decreased EF: 13; without decreased EF:17) C: 15 |
m: 30.7 ± 9.3 (87% M); C; 32.9 ± 8.2 (73% M) |
Not indicated | 3 | DTI/ROI based on TBSS | Participants with EF decrements demonstrated significantly decreased FA in prefrontal white matter, CC and cingulum bundle structures compared with mTBI participants without EF decrements | LOC may be a risk factor for reduced EF as well as associated changes to ventral prefrontal white matter | [56] |
| m: 21 C: 22 |
m: 33.2 ± 12.4 (2/19) C: 31.5 ± 11.7 (2/20) |
Within 3 days | 1.5 | MRS/ROI | Significant decrease in NAA was found in both frontal lobes and in NAA/Cre ratio in the right frontal lobe; lower NAA was found in upper brainstem in the subgroup of patients with post-traumatic unconsciousness; regions contain both GM and WM | Correlation between metabolite changes and cognitive decline and presence or absence of loss of consciousness in acute phase | [57] |
| m: 103 (ES: 43, LS: 33, Ch: 27); C: 21 |
m(ES): 40.63 ± 17.31(10/43); m(LS): 37.64 ± 16.60 (10/43) Ch: 40.11 ± 17.33 (9/27) C: 39.76 ± 18.04 (8/21) |
ES: 5.44 ± 3.15 days LS: 37.00 ± 12.26 days Ch: 195.30 ± 19.60 |
3 | MRS/3D PRESS | Reduced Cho/Cr in Subacute phase in CSV; positive association of Cr (in ES) in the centrum semiovale with chronic automated neuropsychological assessment metrics | Metabolic measurements in centrum semiovale can potentially serve as diagnostic and prognostic markers in mTBI | [58] |
| m: 76 (44 without intracranial lesions; 32 with intracranial lesions: 32) C: 50 |
Without lesions: 31.2 ± 9.5 (17/27); with lesions: 33.9 ± 12.0 (9/23) C: 28.7 ± 9.2 |
11.2 ± 3.3 days | 3 | DTI/Voxel-wise and ROI | Lower FA in GCC, UF and anterior CR bilaterally as well as right IC and EC in patients with intracranial lesions compared with controls; no difference in the DTI parameters between subjects with an without intracranial lesions | For subset of patients lacking neuropsychiatric and substance abuse history, MRI surpassed all other predictors for both 3- and 6-month outcome | [42] |
| m: 21 (with concussion) C: 16 |
Concussed: 20.19 ± 1.03 (0/21) C: 19.9 ± 1.67 (0/16) | 2 days, 2 weeks and 2 months | 3 | DTI/TBSS | Regions implicated are all in right hemisphere: posterior limb of the IC, retrolenticular part of IC, sagittal stratum (ILF, IFOF) and ATR | Support the hypothesis of increased RD and reduced FA within 72-h post injury, followed by recovery that extended beyond 2 weeks; RD appears to be sensitive measure of concussive injury | [59] |
| m: 69; C: 21 |
m: M: 18; range of 10–38; F: 16.7 with range of 12–25 (22/47); C: M: 17 with range of 6–42; F: 17 with range of 7–44 (11/10) | Not indicated | 1.5 | DTI/TBSS | Lower FA value in in males compared with females | Relative sparing of the UF is seen in females compared with male patients, with sex and FA in UF as stronger predictors of TSR than initial symptom severity | [60] |
| m: 62 C: 59 |
m: 30.4 ± 8.8 (17/45) OI: 29.2 ± 9 (14/45) |
27.1 ± 13.7 h and 97.9 ± 17.57 days | 3 | DTI/TBSS MTR MRS based on 2D phase encoding |
At baseline, MD was significantly higher in mTBI cohort relative to comparison group in several WM regions that included IC, superior CR, anterior CR, posterior CR, IFOF, ILF, forceps major and forceps minor of CC, SLF and CST in the right hemisphere MTR, MRS and volumetry did not show significant differences between groups and at different time points in the same group |
Number of WM tracts are affected in mTBI in acute phase of injury and these changes disappear by 90 days none of the MRI modalities used in this study, with the exception of DTI, is sensitive in detecting changes in the acute phase of mTBI | [30] |
| m: 36 OI: 37 |
m: 29.0 ± 8.4 (13/23) OI: 29.4 ± 9.2 (10/27) |
∼24 h and ∼90 days | 3 | DTI/ROI based on atlas Volumetry |
Elevated MD in CR | Potential utility of DTI to capture transient edema in CR | [61] |
| m: 45 (38: neuropsychiatric symptoms; 32: irritability; 32: depression; 18: anxiety. Of these, 13 patients had only irritability, one had only depression, 14 had comorbid irritability and depression, seven had comorbid anxiety and depression, and one had comorbid irritability and anxiety. Ten patients fulfilled the criteria for all three conditions) C: 29 |
m: range 11–47 (11/27) C: 10–28 (8/21) |
Median 20 days (range 0–506 days) | 1.5 | DTI/ROI based on TBSS | Compared with controls, mTBI patients with depression had decreased FA in the superior longitudinal fasciculus, WM around the nucleus accumbens and anterior limb of IC | Detection of the central white matter injuries that underlie depression and anxiety, but not irritability, indicates that not all neuropsychiatric symptoms after mTBI are result of discrete white matter injuries | [62] |
| m: 59 (31: with LOC: 28: without LOC) C: 55 (blast exposed without mTBI) |
M (without LOC: 29.6 ± 7.7) (1/30); with LOC: 27.9 ± 4.2 (0/28); C: 30.5 ± 6.7 |
m: (without LOC): 12.6 ± 12.2 months m (with LOC): 7.2 ± 8.6 months C: 9.4 ± 11.7 months |
3 | DTI/appears like voxel-wise analysis | Reduced FA in left retrolenticular part of the internal capsule | These results support postmortem reports of diffuse axonal injury following mTBI and suggest that injuries with LOC involvement may be particularly detrimental to white matter integrity These results also suggest That LOC-associated WM abnormalities influence neurocognitive function |
[63] |
| m: 38 C: 20 |
m: 33.37 ± 6.44 (5/33) C: 29.35 ± 5.49 (10/10) |
m: 90.92 ± 48.23 days | 3 | DTI/tractography | No significant differences in FA between the C and m groups in brainstem white matter tracts (i.e., medial lemniscus-central tegmentum); CST, and pontine tegmentum | Collectively, these data point to important neurobiological substrates of the chronic and complex constellation of symptoms following mTBI in veterans | [64] |
| m: 23 C: 20 (OI) |
m: 13.2 ± 1.8 (2/21) C: 12.7 ± 1.5 (5/15) |
m: 45.0 ± 17.6 h OI: 48.2 ± 21.1 h |
3 | Voxel-wise analysis | m group had significantly higher FA and AD in middle temporal gyrus WM, superior temporal gyrus WM, anterior CR and SLF; m group had also significantly lower MD and/or RD in a few WM regions including the middle frontal gyrus WM and anterior CR | Alterations of diffusivity in spatially heterogeneous WM regions shortly after mTBI in youth may reflect restrictive water diffusion in WM early post injury | [65] |
| m:40 C: 50 |
m: 38.03 ± 13.69 (16/24) C: 29.88 ± 10.75 (12/38) |
74.43 ± 103.37 h | 3 | DTI/tractography | Major WM tracts include CC, and SLF and ILF | Increased interactions among action–emotion and action–cognition as well as within perception networks; suggests that mTBI may result in changes of structural and functional connectivity on a connectome scale at the acute stage | [66] |
| m: 11 (sustained concussion during the study) C: 24 |
21.2 ± 3.1 (20/25) | 72 h, 2 weeks, 2 months | 3 | Myelin water imaging | Reduction in myelin water fraction at 2 weeks post injury relative to preseason scans in the SCC, right posterior thalamic radiation, left superior CR, left SLF and left posterior limb of IC Myelin water fraction recovered to preseason values by 2 months post injury | Indicate transient myelin disruption following a single mTBI, with subsequent remyelination of affected neurons; myelin disruption was not apparent in the athletes who did not experience a concussion, despite exposure to repetitive subconcussive trauma over a season of collegiate hockey; findings may help explain many of the metabolic and neurological deficits observed clinically following mTBI; myelin disruption was not apparent in the athletes who did not experience a concussion, despite exposure to repetitive subconcussive trauma over a season of collegiate hockey | [67] |
| m: 74 (57 with PTM and 17 without PTM) C: 42 (22 healthy controls and 20 migraine controls) |
m: 18 with a range of 10–47(23/51) C: Healthy controls 18.8 with a range of 6–44 (12/10) Migraine controls 21.7 with a range of 16–43 (10/10) |
20 days (range: 0–506 days) | 1.5 | DTI/Whole brain FA histogram and Shanon Entropy | – | SE more accurately reveals mTBI than mean FA, more accurately reveals those patients with mTBI who develop PTM, and inversely correlates with time to recovery | [68] |
| m: 79 OI: 64 |
m: 29.6 ± 8.8 (24/55) OI: 28.8 ± 8.5 (17/47) |
25.9 ± 12.3 h 94.4 ± 8.7 |
3 | Tractography | FA and MD in left and right UF, left and right IFOF and G CC | LOC was significantly related to MD in UF and IFOF and to FA in left UF and right UF Between-group differences in MD were significant for left UF, left and right IFOF and genu of CC on initial DTI, but not at 3 months post injury; these differences were specific to mTBI subgroup with LOC; early DTI may provide a biomarker for mTBI with LOC, even in patients whose consciousness recovers by arrival in the emergency department; MD better differentiates mTBI from OI than FA on early DTI, but this is specific to mTBI with LOC | [69] |
| m: 56 (43: passed PVT; 13: failed PVT) C: 23 |
m:PVT passed: 32.9 ± 8.2 (7/16); PVT failed 31.5 ± 8.5 (1/12) C: 32.9 ± 7.9 (7/16) |
m PVT passed: 64.4 ± 43.8 mos; PVT failed: 34.0 ± 20.3 months |
3 | DTI/tractography | Anterior IC, cingulum and CC | WM abnormalities are evident in those who failed PVTs; poor PVT performance does not negate the possibility of underlying WM abnormalities in mTBI | [70] |
| m: 3 C: 18 (three groups of 6, one for each m patient) |
m: 44.0 ± 9.1 (1/2) C: 54.2 ± 3.9/34.7/43.0 ± 2.9 ± 4.8/(6/12) |
2 and 3 months | 1.5 | DTI/tractography | Inferior cerebellar peduncle | Fiber number of the ICPs decreased by more than 2 SD compared with those of subjects in the control group; evaluation of ICP tractography would be useful in patients with a balance problem | [71] |
| m: 102 C: 30 |
m: 47 ± 20 (32/70) C: 50 ± 20; 38.1 ± 10.3 (F) (16/14) |
21 ± 15 days | 3 | DTI/TBSS, single fiber skeleton and whole brain | Decreased FA, increased MD, RD and AD, globally | mTBI is associated with changes in WM; correlation between DTI changes outcome | [72] |
| M: 25 (sports related concussion) C: 15 |
m: 21.2 ± 3.1 (0/25) C: 22.9 ± 2.3 (9/6) |
72 h, 2 weeks, 2 months | 3 | FLAR, SWI, volumetric | Small reduction in brain volume at 2 weeks and 2 months; no WMH or microbleeds | – | [73] |
AD: Axial diffusivity; AOC: Alteration of consciousness; ATR: Anterior thalamic radiation; BE: Blast exposed; BI: Blast injury; C: Controls; CC: Corpus callosum; Ch: Chronic; Cho: Choline; Cr: Creatine; CR: Corona radiata; CST: Corticospinal tract; CSV: Centrum semiovale; DTI: Diffusion tensor imaging; DKI: Diffusion kurtosis imaging; EC: External capsule; EF: Executive function; ES: Early subacute; F: Female: FLAIR: Fluid attenuation by inversion recovery; FOF: Fronto-occipital fasciculus; GCC: Genu of the corpus callosum; GO: Good outcome; HARDI: High angular resolution diffusion imaging; IC: Internal capsule; ICP: Inferior cerebellar peduncle; IFOF: Inferior frontal occipital fasciculus; ILF: Inferior longitudinal fasciculus; LOC: Loss of consciousness; LS: Late subacute; M: Male; m: mTBI; MD: Mean diffusivity; MDP: Major depression; MPF: Macromolecular proton fraction; MRS: Magnetic resonance spectroscopy; MTR: Magnetization transfer ratio; OI: Orthopedic injured; PCD: Postconcussion disorder; PCS: Postconcussion syndrome; PO: Poor outcome; PPCS: Persistent postconcussive symptom; PRESS: Point-resolved spectroscopy; PTM: post traumatic migraine; PTSD: Post-traumatic stress disorder; PVT: Performance validity test; RD: Radial diffusivity; ROI: Region-of-interest; SCC: Splenium of corpus callosum; SE: Shannon entropy; SLF: Superior longitudinal fasciculus; SWI: Susceptibility weighted imaging; TBSS: Tract-based spatial statistics; TSR: Time to symptom resolution; UF: Uncinate fasciculus; WM: White matter; WMH: WM hyperintense lesion.