Diffusion tensor imaging findings in semi-acute mild traumatic brain injury.

Journal of Neurotrauma Diffusion Tensor Imaging Findings in Semi-Acute Mild Traumatic Brain Injury (doi: 10.1089/neu.2014.3337) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.

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1 Diffusion Tensor Imaging Findings in Semi-Acute Mild Traumatic Brain Injury

Andrew B. Dodd 1, Katherine Epstein 1, Josef M. Ling 1 and Andrew R. Mayer 1,2,3*

1

The Mind Research Network/Lovelace Biomedical and Environmental Research Institute,

Albuquerque, NM 87106 2

Neurology Department, University of New Mexico School of Medicine, Albuquerque, NM 87131

3

Department of Psychology, University of New Mexico, Albuquerque, NM 87131

Running Head: DTI Findings in Semi-Acute mTBI

*Corresponding author: Andrew Mayer, Ph.D., The Mind Research Network, Pete & Nancy Domenici Hall, 1101 Yale Blvd. NE, Albuquerque, NM 87106; Tel: 505-272-0769; Fax: 505272-8002; Email: [email protected]

KEYWORDS: mild traumatic brain injury; concussion; diffusion tensor imaging; anisotropic diffusion; review


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2 Abstract The past 10 years have seen a rapid increase in the use of diffusion tensor imaging to identify biomarkers of traumatic brain injury (TBI). Although the literature generally indicates decreased anisotropic diffusion at more chronic injury periods and in more severe injuries, considerable debate remains regarding the direction (i.e., increased or decreased) of anisotropic diffusion in the acute to semi-acute phase (here defined as less than 3 months post-injury) of mild TBI (mTBI). A systematic review of the literature was therefore performed to 1) determine the prevalence of different anisotropic diffusion findings (increased, decreased, bi-directional or null) during the semi-acute injury phase of mTBI and to 2) identify clinical (e.g., age of injury, post-injury scan time, etc.) and experimental factors (e.g., number of unique directions, field strength) that may influence these findings. Results from the literature review indicated 31 articles with independent samples of semi-acute mTBI patients, with 13 studies reporting decreased anisotropic diffusion, 11 reporting increased diffusion, 2 reporting bi-directional findings and 5 reporting null findings. Chi-squared analyses indicated that the total number of diffusion-weighted (DW) images was significantly associated with findings of either increased (DW ≥ 30) versus decreased (DW ≤ 25) anisotropic diffusion. Other clinical and experimental factors were not statistically significant for direction of anisotropic diffusion, but these results may have been limited by the relatively small number of studies within each domain (e.g., pediatric studies). In summary, current results indicate roughly equivalent number of studies reporting increased versus decreased anisotropic diffusion during semi-acute mTBI, with the number of unique diffusion images being statistically associated with the direction of findings.


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3 Introduction There can be no doubt of the recent sea change that has occurred in the study of mild traumatic brain injury (mTBI), also commonly referred to as concussion. It was initially reported that mTBI did not result in long-term behavioral or neurological consequences,1 except for in a small percentage of patients with pre-existing psychiatric conditions.2;3 Standard clinical neuroimaging sequences (Computed Tomography scans; T1- and T2-weighted images) are typically negative for the majority of mTBI patients,4;5 which further helped propagate the view that mTBI did not lead to neuronal pathology. More recent studies suggest that the very longterm effects of concussion may be greater than initially believed,6;7 with a dramatic increase in the diagnoses of chronic traumatic encephalopathy (CTE) amongst recently deceased athletes and some military personnel. Similarly, there has been a proliferation of studies using advanced neuroimaging techniques8;9 and blood-based10;11 bio-markers to identify objective biomarkers of mTBI, with the hope that non-invasive neuroimaging will ultimately provide objective evidence of the so-called “invisible wounds”. To this end, there is accumulating evidence from both animal12;13 and human14-16 studies suggesting subtle white matter (WM) abnormalities following trauma, which are better captured by diffusion tensor imaging (DTI) than by conventional imaging sequences.17 Animal models suggest that axonal pathology is more pronounced in the acute phase of injury,13;18;19 with evidence of injury progression over a 4-6 week period that correlates with cognitive dysfunction.13 These traumatic axonal injuries (TAI) can occur either as a direct result of rotational forces involving axonal stretch, or from complex secondary cellular processes, mechanoreceptor dysregulation and ionic flux. Excellent reviews of these processes are provided elsewhere.20;21


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4 Human and animal DTI studies have frequently utilized metrics of anisotropic diffusion (commonly computed as fractional anisotropy (FA)) and mean diffusivity (MD) as primary outcome measures. Briefly, FA indirectly measures the relative degree of directional motion of water,22;23 with cellular membranes, myelin and the ratio of intracellular to extracellular fluid primarily contributing to the degree of anisotropic diffusion.24 In contrast, MD represents the average distance that water travels, with no regard for the degree of anisotropic diffusion.23 MD is frequently reported as apparent diffusion coefficient (ADC), although the computation of these constructs can vary.16;25 Less frequently studied DTI metrics include axial (AD) and radial diffusivity (RD), which are theoretically believed to capture variance primarily from axonal membranes (AD) versus myelin/extracellular (RD) components.24;26 However, the biological specificity of these metrics are a matter of debate27 and many other non-biological factors such as head motion also contribute to the measurement of diffusion scalars.28 Therefore, human studies of TBI are typically not capable of parsing the exact underlying mechanisms of abnormal DTI findings. Studies have reported both increased and decreased anisotropic diffusion following TBI. However, a few crucial distinctions, such as tissue type, measurement time post-injury and severity of injury can help parse some of the more immediate findings. For example, animal models almost universally indicate reduced anisotropic diffusion in WM.12;19;29 Although many different types of pathology affect diffusion metrics, findings of reduced FA are most commonly attributed to underlying cellular changes to membrane structures and/or edema.12;13;19;30;31 However, it is important to note that animal models more carefully replicating the mechanical forces experienced in more mild forms of injury have only been recently developed.32-34 Specifically, previous animal injury models frequently induced cortical


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5 contusions or other parenchymal alterations of sufficient severity that they are visible with MR, suggestive of more severe injuries in human TBI.4 Similar to the animal literature, there are fairly consistent findings of reduced FA and increased MD in WM during the chronic phases of mild, moderate and severe TBI in humans14-16;35;36 (see Lo et al. (2009)37 for contrary evidence). Human studies of severe TBI also tend to report reduced FA in WM both during the acute and semi-acute stages of injury.36;38 Reports of increased anisotropic diffusion in animal models of TBI have almost exclusively been observed in grey matter,12;29;39;40 including some studies that also observed reduced anisotropic diffusion in WM.12;29 Increased anisotropic diffusion and/or decreased ADC in grey matter have typically been attributed to cytotoxic edema, reflecting alterations in the ratio of intracellular relative to extracellular water,40;41 or to reactive gliosis,12;29 reflecting a more symmetric arrangement of typically amorphous glial cells following injury. Findings of increased anisotropic diffusion and/or decreased ADC within grey matter have also been observed in semiacute mild42;43 and more severe30;44 human TBI studies. In contrast to the above, DTI studies of WM injury during the acute/semi-acute phase of mTBI has resulted in findings of increased diffusion, decreased diffusion, bidirectional and null results. The main focus of the current review paper is to provide a comprehensive overview of this burgeoning field (Figure 1), as well as semi-quantitative analyses of clinical and methodological factors that may influence findings. To further motivate our semi-quantitative analyses, we first provide a general overview of some key clinical and experimental issues in DTI studies of mTBI. Potential Factors Affecting DTI Findings in Research


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6 As intimated by previous groups,45 the field of mTBI research is dominated by many clinical and experimental challenges. Foremost, the definitions for diagnosing mTBI are still being actively debated by multiple governing bodies,46;47 which has resulted in heterogeneity in the severity of injury within the mTBI group. Patients only dazed following a blow to the head, patients unconscious for up to 30 minutes, and patients with large subdural hematomas can all be classified as having experienced a mTBI under current rating systems. However, the underlying neuropathology, neurobehavioral sequelae and recovery trajectories are likely to be very different across these three patient types, especially for patients with positive findings (i.e., complicated mTBI) on traditional neuroimaging.48 Similarly, recent evidence suggests that there are likely to be differences in the neuropathology and the course of recovery (short and longterm) between patients who received a single mTBI (e.g., more typically occurring in an emergency room cohort) and patients who received temporally proximal, repetitive mTBIs or subconcussive head injuries (e.g., athletes and military personnel7). Athletes with a history of concussion report more baseline symptoms than those with no history of concussion,49 and repeat concussions within the same sport’s season increases the risk of long-term cognitive and psychiatric dysregulation by 1.5 to 3 fold relative to athletes with a single concussive incident.50 Over the lifespan, cumulative effects of repetitive mTBIs result in a four-fold increase in neurodegenerative disease51 and a unique neuropathological syndrome involving tauopathies in periventricular spaces and deep cortical sulci.7 A second major source of variability involves the time post-injury when patients are recruited into studies. Human mTBI studies frequently utilize very liberal time post-injury inclusion criteria that can range from days to weeks to years post-injury, even within the same study. On traditional concussion measures (e.g., balance and neurocognitive testing), most (80-


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7 95%) patients experience a rapid and spontaneous recovery in the first few days to weeks postinjury as documented by several meta-analyses52-54 and large sample studies.55;56 Thus, imaging patients that are symptomatic more than 3 months post-injury represents a subset of the population, with findings that may or may not generalize to the majority of mTBI patients typically evaluated in the emergency room and sports-concussion clinics who will eventually recover (defined here as a return to baseline levels). However, it should be noted that some more recent research estimates indicate that as many as a third of mTBI patients remain symptomatic at 3-months post-injury.57 In addition, animal models indicate clearly different recovery trajectories for various injury biomarkers.20 For example, an animal would be classified as “recovered” approximately 15 minutes post-injury based on glutamate levels, whereas cerebral blood flow is still typically abnormal up to one week post-injury (the neurometabolic cascade). Therefore, sampling mTBI patients at different intervals post-injury may at best introduce additional variability, or potentially confound different recovery trajectories. A third major concern is that the data acquisition parameters and analytic techniques used for DTI data may also influence results. Early mTBI studies and studies conducted in clinical settings may utilize a small number of diffusion weighted (DW) directions, resulting in a low angular resolution. However, both simulations and in-vivo experiments demonstrate that DW schemes with 30 or more directions provide more accurate estimation of diffusion scalars by decreasing measurement error.58;59 These errors are more evident within regions of high anisotropy and/or under conditions with poor signal-to-noise characteristics.58 Although the sampling scheme should not directly affect group-wise comparisons from a statistical perspective (i.e., internal validity), it may interact with underlying biological mechanisms associated with trauma such that certain biological mechanisms may be more readily


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8 apparent under a particular sampling scheme (e.g., higher b-values). Moreover, the number of DW directions is also likely to be correlated with other methodological factors (e.g., field strength, year data was collected, sophistication/understanding of optimal post-processing techniques) that are also likely to influence results. Summary of Current Diffusion Research Findings in Semi-acute mTBI The current review focused on studies that were 1) published prior to 11/1/2013 and 2) reported findings on anisotropic diffusion in WM during the first three months following mTBI. Three months was operationally chosen as the cut-off based on clinical (i.e., DSM-IV criteria) definitions of a persistent post-concussive syndrome that indicate symptom chronicity. Using these criteria as guidelines, literature searches were conducted using variations of “DTI”, “mTBI”, and “concussion” in article titles, abstracts, and keyword lists. We excluded studies investigating the more chronic injury phase of mTBI given the relative consistency of findings (i.e., reduced FA) and the recent reviews on this topic.14;16;35 Following this initial search, articles were reviewed for appropriate population and time post-injury before the final decision for study inclusion was made. For all relevant articles, Google Scholar was also utilized to search for citation history and identify additional articles. Two articles were eliminated from the search that had an appropriate population but presented a single case study of mTBI60;61 in conjunction with other participants receiving subconcussive head blows. Another study62 was excluded because the mean post-injury interval (2.9 months) and standard deviation (2.4 months) suggested that a large percentage of patients would exceed the 3-month scan interval used for the current review. Articles that included a mTBI


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9 cohort amongst moderate or severe patients were included if data from the population of interest could be parsed out of the broader results.63-65 Of the 37 published reports that met study inclusion criteria (see Table 1), several papers appeared to report results from different WM tracts and/or neuropsychological measures using an identical or similar patient cohort as primarily determined by subject demographics (e.g., identical age of patient group, days post-injury) and/or as directly referenced within the publication. Specifically, there have been separate reports of decreased anisotropic diffusion in adults,66;67 increased anisotropic diffusion in adults,68;69 increased anisotropic diffusion in pediatric mTBI patients70-73 and increased anisotropic diffusion in pediatric sports-related concussions74;75 that were based on similar samples. While results from all of these studies are reviewed, only findings from the original cohort were included in the semi-quantitative analyses to reduce reporting bias (i.e., artificially inflating the number of true observations). Importantly, directional findings (i.e., increased or decreased FA) for all secondary publications were consistent with the original study. In addition, one study reported results from an independent sample of adult mTBI patients76 in conjunction with pooled results from a previous cohort,68 and was therefore included as a separate study in analyses. To facilitate the following review, major WM tracts were standardized to the abbreviations contained in Table 2. Similarly, broad categories were also developed to discuss whether the patients were primarily derived from emergency room settings (ER), sports-related (SR) injuries or military (MIL) samples. Results from other DTI scalars (MD, AD and RD) and other experimental factors/results are presented in Supplemental Table 1 (expanded version of Table 1).


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10 Studies Reporting Reduced FA in Semi-Acute mTBI In a seminal study of DTI in mTBI, Arfanakis and colleagues scanned 5 adult ER patients injured within 24 hours.77 The authors performed region of interest (ROI) analyses of WM tracts, reporting decreased FA in the anterior and posterior portions of the IC and CC of mTBI patients relative to both controls and the hemisphere contralateral to injury. These differences were no longer significant in 2 mTBI patients who returned 30 days post-injury. Inglese and colleagues examined 20 adult ER mTBI patients between one and ten days post-injury, assessing FA and MD in whole-brain histograms and ROI corresponding to the CC, IC and CS.66 The authors reported decreased FA in the splenium and posterior IC and increased MD in the splenium. A reanalysis of the same patient pool reported decreased FA and increased MD in the CC, IC and CS using a ROI approach.67 Miles also reported a positive correlation between baseline FA and neuropsychological outcome (executive functioning) at 6-months follow-up, as well as a trend between MD and response speed. In a study encompassing multiple grades of TBI, Kumar and colleagues scanned 26 ER mTBI patients within two weeks of injury.78 They analyzed FA, MD, RD, and AD metrics in seven CC ROI. While they found no evidence of changed AD and MD, they reported increased RD in ROI corresponding to the genu and splenium and decreased FA in the genu only. DTI scalars were negatively correlated with number and figure connection tests, though the neuropsychological measures were obtained from as much as 6 months post-injury. Twenty adult ER patients were scanned by Lipton and colleagues 2 to 14 days post-injury using whole-brain voxelwise analyses of FA and MD.79 The authors reported decreased FA with a corresponding increase in MD in 15 clusters relative to the control group, with 5 clusters occurring in the frontal lobe. Patients also made significantly more errors on a test of executive function, a measure


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11 correlating with decreased FA in some, but not all, identified clusters. Singh and colleagues investigated DTI metrics (FA, MD, AD, and RD) in a group of 12 adult ER mTBI patients scanned approximately one month post-injury using ROI identified through whole brain tractography.80 Tracts in the ILF, IFO, SLF, genu and splenium of CC, fornix and hippocampus showed a decrease in FA and increase in MD, with a less pronounced but significant increase in both AD and RD. Following increased interest in wartime casualties, MacDonald and colleagues assessed DTI metrics in 63 mTBI military patients who suffered blast-related trauma (median 14 days), with 75% of patients returning 6 to 12 months for a follow-up scan.81 ROI analysis focused on the CC, CB, UF, anterior and posterior IC, and CP, examining for significant changes in FA, AD, RD, and MD. A significant decrease in FA was observed in the bilateral middle CP, with increases in RD and MD also observed for several other WM tracts. FA remained significantly decreased at a second follow-up visit, whereas RD and MD were no longer statistically significant. In contrast, AD was not significant during the semi-acute injury stage but did exhibit evidence of being lower at the second visit. In a study of 20 mild and moderate TBI patients, Matsushita and colleagues scanned 9 adult mTBI patients 3.5 days post-injury to investigate FA changes in the CC, IC, frontal and occipital WM using a ROI approach.64 Decreased FA was reported within the splenium of mTBI patients, which also correlated with a measure of intelligence. Smits and colleagues compared DTI metrics (FA and MD) with scores on the Rivermead Post Concussion Symptoms Questionnaire (RPCSQ), a measure of post-concussive symptom severity, in 19 ER patients scanned within 40 days of injury using TBSS.82 They found a decrease in FA in the right IFO, as well as a negative correlation between RPCSQ score and FA (IFO, IC, right splenium and UF)


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12 and a positive correlation with MD (left IFO, ILF, SLF). A study conducted by Messé and colleagues also utilized TBSS to investigated WM changes in 53 ER patients scanned eight to twenty-one days post-injury.83 They reported decreased FA in nine WM tracts (CC, CP, IC, EC, CR, thalamic radiation, sagittal striatum, fornix, and SLF) and increased RD and MD in both the CC and the SLF. AD was not significant for any regions. The authors also found that differences between mTBI and controls normalized from the initial scan to a scan performed 6 months postinjury. Stevens and colleagues utilized joint independent component analysis to assess functional connectivity and changes in FA in a group of 30 adult ER mTBI patients injured approximately two months prior to scan.84 Using archival control data for comparison, they noted decreased FA in areas corresponding to the right precentral/postcentral gyrus, left parietal precuneus and right posterior CR. More recently, Kurki and colleagues utilized diffusion tensor tractography of the UF to investigate changes in 29 mTBI patients (selected from a larger cohort of 110 patients) scanned an average of 23 days post-injury.63 The investigators found a significant decrease in FA and increase in MD in the UF. In addition, a negative correlation existed between measures of volume and FA in the left UF, whereas a positive correlation existed between volume and MD bilaterally. In a longitudinal study by Grossman and colleagues, 20 ER patients were imaged within one month of injury, with approximately 50% returning for a second visit 9 months post-injury.85 FA and MD metrics were analyzed for the thalamus, IC, EC, CC, CS, CB, optic radiations and total WM throughout the brain using both ROI and TBSS approaches. A significant decrease in FA and increase in MD were discovered in each of these regions. Longitudinal data was mixed when compared to baseline, with MD significantly decreased in the thalamus and IC, but


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13 increased in the CC and total WM. FA was more consistent, showing signs of normalization (i.e., increases) in the thalamus and total deep grey matter. Another recent longitudinal study (72 hours and approximately one-month post-injury) compared DTI metrics (FA and MD) between 14 mTBI patients and matched controls using TBSS.86 The authors reported decreased FA and increased MD at time one relative to controls in WM tracts bilaterally and at time two relative to controls in the right hemisphere only. A decrease in FA and increase in MD was also observed in the anterior CC, right CR, and IC for mTBI patients between the 72-hour and one-month acquisition scans. Studies Reporting Increased FA in Semi-Acute mTBI The initial study indicating increased FA during the semi-acute stage (three days post) of mTBI was conducted in a sample of six adult ER patients.87 Increased FA was observed in the posterior CC during both VBM and ROI analyses. Wilde and colleagues assessed FA, MD and RD in a sample of 10 pediatric ER patients scanned between one and six days post-injury.71 Focusing on an ROI corresponding to the entire CC, the authors reported increased FA, and increased and decreased MD/RD. Scores on the RPCSQ were also positively correlated with FA and RD.71 Other researchers reanalyzing the same pool of patient data have reported increased FA in the fornix (significant) and CB (marginally significant), as well as significantly decreased MD in the fornix and CB bilaterally.70;72;73 Building upon their previously published research into use of texture analysis,88 Holli and colleagues examined DTI scalars and neuropsychological performance in 42 semi-acute (less than three weeks post-injury) adult ER patients.89 FA and MD values were measured in ROI corresponding to the CC, CS and mesencephalon bilaterally. Increased FA and decreased MD


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14 were observed within the left mesencephalon, and FA positively correlated with texture analysis parameters and a composite verbal memory score. A study of the effects of post-concussive symptoms on FA measures by Hartikainen and colleagues separated a group of 18 ER mTBI patients (all scanned less than three weeks post-injury) into symptomatic and asymptomatic patients.90 Although the authors discuss recruiting both mild and moderate TBI patients,90 patients were classified as having sustained a moderate injury on the basis of a positive CT scan (herein referred to as complicated mTBI). ROI corresponded to the thalamus, IC, CS and mesencephalon bilaterally. FA was increased and MD was decreased in the mesencephalon in symptomatic patients relative to their asymptomatic counterparts. Mayer and colleagues investigated longitudinal changes in FA, RD and AD in 22 adult ER patients injured in the previous three weeks.68 Primary analyses focused on ROI in the CC, SLF, CR, UF and IC, and premordid intelligence was used as a covariate for all analyses. Increased FA was noted in the genu, left superior CR, left CR and left UF, while decreased RD was noted in only the genu, left CR and left UF. There were no significant differences between patients and controls in AD or MD, or for secondary voxelwise analyses (TBSS) of FA. Longitudinal scans were obtained in 59% of patients three to five months post-injury, with results suggesting partial normalization in FA values of the splenium and CR when comparing patients to their baseline measurement. A paper focusing on both functional (functional magnetic resonance imaging (fMRI)) and structural (DTI) connectivity within the default-mode network and frontal areas was published by Mayer and colleagues using a similar cohort in the following year.69 Results from this mostly overlapping sample included increased FA in the anterior CR and EC at initial measurement, with some evidence of partial normalization at follow-up. Ling and colleagues76 utilized an independent sample of 28 ER patients scanned within three weeks of


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15 injury and an independent sample of matched controls in an attempt to replicate the original findings from the Mayer group.68 No significant group differences were again observed on voxelwise tests of WM.76 In addition, the finding of increased FA and reduced RD within the genu of the CC was replicated in the independent sample, with additional non-significant trends of increased FA in the right CR and IC. However, significant findings of increased FA in the left-hemisphere ROI (superior CR, CR and UF) from the original sample failed to replicate. In a study of SR concussion, Henry and colleagues scanned 16 college athletes within a week of injury.91 They investigated metrics of FA, AD, and MD using a voxelwise approach focused on WM. Increased FA was noted in the genu and body of the CC, as well as in WM tracts extending from primary motor and sensory cortices towards the thalamus in the right hemisphere. Decreased MD was noted in only the body of the CC, while increased AD was observed in tracts underlying the primary motor cortex. These findings remained relatively stable across a six month follow-up period. Wilde and colleagues conducted a unique study investigating short-term changes in DTI metrics by sampling uncomplicated ER patients every other day within the first week of injury.92 Values of FA, MD, AD and RD were analyzed in ROI corresponding to the CB. FA had a generally increased trajectory from the first measurement in the CB, while measures of AD, MD and RD were less consistent. Subjects also showed a reliable dip and rebound in Hopkins Learning Verbal Test-Revised (HLVT-R) verbal memory scores from the time of first measurement. Mayer and colleagues also examined an independent cohort of 16 pediatric ER patients approximately two weeks post-injury.93 ROI analysis (FA, RD and AD) focused on the CC, CR, CB, IC, and CP, with voxelwise and TBSS analyses of FA in WM. The authors reported increased FA and decreased RD for patients relative to controls in the right anterior CR


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16 (including a nonsignificant trend in the left superior CR), increased FA in the left CP, decreased RD in the left anterior CR, and a nonsignificant trend of decreased RD in the CP. Significantly increased FA was also observed in numerous WM tracts throughout the JHU WM atlas during voxelwise comparisons. In a more recent study of outcomes of uncomplicated mTBI in adults, Waljas and colleagues collected DTI data (FA and MD) on a cohort of 48 patients injured a month prior to scan.94 A priori ROI included the bilateral CC (body, splenium, and genu), IC, CP, CR, CS, UF, and forceps. Patients exhibited significantly higher FA in the splenium and lower MD in the genu. Although a variety of neurocognitive measures were obtained, none of the measures were significantly correlated with the diffusion findings. In two recent papers,74;75 12 pediatric hockey players sustained SR injury an average of 35 days prior to scan. The Virji-Babul paper performed a whole-brain voxelwise analysis of FA and MD metrics, while the Borich paper addressed metrics of FA, RD, AD and MD using TBSS. Both papers reported increased FA and decreased MD in patients relative to controls, with TBSS analyses indicating significantly decreased AD and marginally decreased RD. TBSS analysis also uncovered specific areas of increased FA mostly in the prefrontal cortical areas of patient brains, which were negatively correlated with a measure of concussion symptoms in sports injury (SCAT2). Studies Reporting Bidirectional FA in Semi-Acute mTBI Two studies have reported both increased and decreased FA in the same cohort of patients. Lipton and colleagues used z-scores to identify regions of abnormal diffusion in a group of 34 adult ER patients that were injured in the last two weeks.95 Areas of increased FA were frequently observed in the anterior and superior CR, genu and body of the CC, and in frontal


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17 WM. Decreased FA was frequently seen in the anterior and superior CR, IC and splenium of the CC, as well as in frontal WM. The investigators also followed up with patients at three months and six months (47% and 29% returning, respectively). At three months, the majority of patients had more voxels with increased FA and fewer with decreased FA as compared to their initial scans. At six months, the number of increased FA voxels remained increased but showed signs of stabilizing. McAllister scanned 10 pediatric and adult athletes prior to injury and within 10 days of injury.96 Participants in the study were also equipped with helmets to record impact strength and velocity during practices and games. The researchers reported both increased and decreased FA/MD between pre- and post-concussion scans in an ROI corresponding to the CC. The magnitude of change was positively correlated with the strain rate and maximum strain rate measured with the helmets (ΔFA) and with the strain and maximum strain (ΔMD). Studies Reporting Null FA Findings in Semi-Acute mTBI Other studies have reported null findings during the semi-acute stages of mTBI. In a study by Rutgers and colleagues across all degrees of TBI severity, 12 adult mTBI patients were scanned within three months of injury.65 The researchers examined ROI in the CC, examining both FA and MD metrics. Although decreased FA was observed in the CC for moderate and severe TBI, there were no significant differences between mTBI patients and controls. In a multimodal study of functional deficits in SR concussion, Zhang and colleagues examined FA and MD changes in 15 college athletes concussed within the last 30 days.97 ROI analysis included the CC and some grey matter areas (PFC and V1) identified in an fMRI analysis of the same data. TBSS was also used to examine WM changes. Although decreased MD was observed in the bilateral dorsolateral PFC, there was no difference between patients and controls on WM FA. Another multimodal study of SR concussion was conducted on a group of 12 pediatric


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18 patients two to three days post-injury, focusing on ROI in the IC and CC.98 While the researchers found significant differences between patients and controls in other imaging modalities, FA, AD and RD were not significantly different across the groups. In addition, the authors reported no significant differences in diffusion metrics when 75% of patients were rescanned at two weeks and 30 or more days post-injury (sampling time dependent on symptom resolution). To study post-concussive syndrome (PCS), Messéand colleagues studied a group of 23 ER patients during both the semi-acute (approximately three to four weeks) and early chronic (three to four months) injury stages, classifying patients into good or poor outcome based on resolution of PCS symptoms at time two.99 Measures of FA, AD, RD, and MD for both mTBI groups and a control group were evaluated using grey matter voxelwise morphometry and WM TBSS. Results indicated no significant differences between good and poor outcomes for metrics of FA, AD, or RD. However, increased MD was observed in those with poor outcome relative to controls in the left anterior thalamic radiation, bilateral SLF and bilateral corticospinal tract, while mTBI patients as a whole showed increased MD relative to controls in forceps major and minor and the IFO and ILF bilaterally. Lange and colleagues examined diffusion changes (FA and MD) in a large cohort of semi-acute mTBI patients scanned approximately 1.5 months postinjury relative to orthopedic or soft-tissue injured controls.100 Using a ROI approach focused on the CC, the authors reported a significant increase in MD in the splenium in conjunction with null FA findings. Examination of Clinical and Methodological Factors Quantitative analyses were conducted next to determine whether previously discussed clinical or experimental factors (see Figure 2 and Supplementary Table 2) could differentiate findings of increased or decreased anisotropic diffusion in semi-acute mTBI. Articles reporting


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19 null65;97-100 or bidirectional95;96 anisotropic diffusion findings were eliminated, leaving a total 13 articles reporting decreased anisotropic diffusion and 11 articles reporting increased anisotropic diffusion for final analyses. Shapiro-Wilk tests confirmed no variables were fit for evaluation with parametric tests. Initial analyses also indicated significant colinearity (ρ = 0.531, p = 0.008) between publication year and MRI field strength, such that field strength was not examined further. Clinical and experimental variables were analyzed with either binomial or chi-square tests depending on the number of observations per cell. Specifically, chi-square tests were used to determine whether the number of total DW images (median split = DW ≤ 25 vs. DW ≥ 30), publication year (median split = publication ≤ 2010 vs. publication ≥ 2011) or patient (mTBI only) sample size (median split = N ≤ 19 vs. N ≥ 20) were associated with a higher likelihood of increased or decreased FA. Other clinical and experimental variables (Figure 2), such as study population (ER vs. MIL or SR), mTBI patient age (pediatric vs. adult), presence of positive radiological findings (uncomplicated vs. complicated and mixed mTBI samples) and time postinjury mTBI (0-30 days vs. 31-90 days), type of analysis performed (ROI vs. voxel-based), and the b-value at which DTI was acquired (less than 1000s/mm2 vs. at/above 1000s/mm2), did not have an appropriate distribution for chi-square analyses. These factors were therefore individually compared against the binomial distribution, assuming that an equal number of findings with increased or decreased FA should be observed. Due to the exploratory nature of all analyses, results were not corrected for multiple comparisons. Chi-squared analyses were not significant (p > 0.10) for publication year or patient sample size. However, a significant deviation was observed for the number of total DW images


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20 (p = 0.041), such that 9/12 studies with 25 or fewer total DW images reported decreased FA whereas 8/12 studies with 30 or more DW images reported increased FA. There were no other clinical or experimental variables that significantly (p > 0.10) deviated from the expected binomial distribution in terms of being associated with increased or decreased FA. However, these analyses were frequently restricted by the small number of studies conducted in each particular domain. For example, of the three studies that examined pediatric mTBI and observed uni-directional findings (increased or decreased FA), all three reported increased FA. In contrast, five of the six studies on mixed or complicated mTBI samples reported decreased FA. Discussion DTI has become one of the more widely utilized in vivo neuroimaging techniques for investigating alterations in brain structure following mTBI. In contrast to relatively consistent finding of decreased FA in chronic mTBI or more severely injured TBI cohorts,14-16;35;36 results from the current review indicated mixed findings in the semi-acute (less than 3 months postinjury) phase of mTBI. Specifically, of the 31 studies with independent samples published prior to November 1st of 2013, 13 studies reported decreased FA, 11 studies reported increased FA, 2 studies reported bidirectional FA (both increased and decreased) and 5 studies reported null findings. As reviewed in the introduction, there are multiple biological mechanisms (e.g., vasogenic edema, cytotoxic edema, reactive gliosis, myelin changes and axonal membrane changes) and clinical factors (e.g., head motion, the presence of other medications) that could potentially explain these various DTI findings.12;13;17;26;28;29;40;41;69 Importantly, various reviewed studies have also linked both increased69;71;89;92 and decreased63;64;78;82 FA to cognitive and neuropsychiatric sequelae, such that there is not a clear link between various pathologies and


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21 symptomatology. The goal of the current review was not to provide an in-depth review of these potential underlying biological mechanisms, but rather to assess the relative frequency of anisotropic diffusion findings in the literature and assess how clinical and experimental factors may have influenced these reports. To this end, results from semi-quantitative analyses indicated that the total number of diffusion weighted images was significantly associated with direction of FA, with 30 or more total directions being associated with increased FA and 25 or less directions being associated with decreased FA. Dependent on signal-to-noise ratios and the degree of anisotropy, variance in FA estimates monotonically decreases as a function of the increasing number of gradients, asymptoting at approximately 20 directions.59 Thus, studies utilizing fewer than a total of 20 diffusion weighted images (9 studies in the current review) may result in more variable, and potentially unreliable, estimates of FA. Sequences with low angular resolution are also less able to resolve crossing fibers58 and confound the effects of subject motion101 during the estimation of anisotropic diffusion. Finally, previous data suggests that the number of diffusion weighted images may be differentially sensitive to changes in FA and MD in Parkinson’s patients, with voxelwise abnormalities increasing with the number (unique or repeated) of diffusion weighted images.102 However, it is less clear how the number/angular resolution of DW images interacts with the underlying tissue properties such as edema or tissue damage. Ultimately, this question can only be addressed through animal or in vitro models, where test parameters and the types of injury can be more carefully controlled and measured. In contrast to experimental variables, none of the clinical variables were associated with a significant deviation from expected probabilities in terms of increased versus decreased anisotropic diffusion. However, this may have resulted from the small number of studies


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22 that have been conducted with the different sub-populations of mTBI patients. With this important caveat in mind, both the age at time of injury and the presence of positive radiological findings were suggestive of differing effects on anisotropic diffusion. Specifically, studies on pediatric mTBI have more frequently reported increased FA relative to decreased FA. The vulnerabilities of the developing brain as well as the potential for recovery are unique for children, and pediatric patients may be more susceptible than adults to diffuse injury.103-105 However, the pathological mechanism by which pediatric patients would be more likely to exhibit increased anisotropic diffusion is not clear. Second, the current review also suggests that studies examining complicated mTBI or mixed injury cohorts are more likely to report decreased or bidirectional FA during the semiacute injury stage. The majority of studies on moderate to severe TBI also report decreased FA in WM, and complicated mTBI patients are more likely to have poor outcomes relative to noncomplicated patients.48;106;107 Thus, it is possible that more severe injuries may be associated with increased vasogenic edema and/or structural changes to the axonal membrane that manifest as decreased FA on DTI scans. This may also provide some degree of reconciliation with the animal WM literature, where injuries are typically more severe rather than mild in nature.34 The largest limitation of the semi-quantitative analyses was that stratification was based on imprecise data from previous publications. For example, stratification for time post-injury was done using a mixture of reported means, medians, ranges and maximums. Similarly, a percentage of sports-related injuries are also likely to be present in most ER cohorts, and uncomplicated mTBI versus complicated mTBI are defined differently by individual research groups. The inexact nature of reporting on these variables precluded direct tests across the studies in several instances. Although these limitations are common to most retrospective


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23 reviews of existent bodies of literature, more research is needed that directly examines these issues in large cohorts of patients. Second, there are many other important clinical (e.g., race, gender, etc.) and experimental (e.g., spatial normalization routines, etc.) variables that were not analyzed in the current experiment. Some of these variables could not be examined due to lack of details in published reports whereas others did not include enough variability for analyses. Finally, we did not correct for multiple comparisons when examining clinical and experimental factors that may have contributed to observations of anisotropic diffusion. There are several important considerations and future directions for DTI studies following mTBI. Foremost, studies that combine information across various neuroimaging modalities are needed to capture the multi-faceted pathology of mTBI. For example, DTI can be combined with susceptibility weighted imaging to capture petechial hemorrhages in addition to axonal pathology following mTBI.108;109 When used in conjunction with functional imaging techniques, DTI can also be used to investigate functional/structural relationships as was recently done in concussed veterans with depressive symptoms,110 during working memory paradigms in sports-related injuries97 as well as in studies of functional/structional connectivity following mTBI.69 Similarly, larger, well-powered studies exploring existing DTI metrics and using multimodal neuroimaging in conjunction with a longitudinal design are needed to address the unique recovery trajectories (e.g., faster or slower return to baseline) that characterize different forms of pathology in animal models (the neurometabolic cascade20). Second, it is increasingly recognized that the pattern of white matter injury is likely to vary across individual patients due to the heterogeneous initial injury conditions. However, traditional ROI and voxelwise approaches implicitly assume that clinically heterogeneous patients have a homogenous pattern of image-based abnormalities (i.e., high degree of spatial


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24 overlap). Robust methods for classifying diffusion abnormalities on a patient-by-patient basis have only recently been applied to mTBI,60;111 with the hope that these will increase both the sensitivity and specificity of findings. Therefore, a critical direction for the field will be large N studies that account for heterogeneity in injury location as well as heterogeneity in recovery, even with existing DTI metrics. A third future direction for DTI research will be the development of more standardized data collection protocols and analyses platforms. Both of these steps would permit pooling of data across institutions and settings, ultimately allowing for direct comparisons of different patient populations. Finally, diffusion models that more accurately capture the complexities of underlying biological tissue are also needed to advance the study of semi-acute mTBI. Conventional DTI scans assume that diffusion can be modeled with a mono-exponential (i.e., single b-value sequence) decay, characterizing a Gaussian distribution of diffusion displacement predicated by a homogeneous tissue environment.112 However, 1) biological tissue is complex rather than homogeneous (i.e., intra-axonal space is more complex than extra-axonal space), 2) diffusion is restricted differently depending on tissue complexity,113 and 3) tissue complexity is altered following trauma in animal models.13;114 Non-Gaussian diffusion can arise from restricted diffusion (i.e., membranes and organelles) and the presence of two (i.e., intra-axonal and extraaxonal) compartments with differential diffusion rates.115 Although the validity of the two compartment model for slow (intracellular) and fast (extracellular) diffusion has been questioned, differential rates of intra-axonal (≈ 0.07 µm2/ms) versus extra-axonal (≈ 0.85 µm2/ms) diffusion have been established.116;117 Methods for determining intra-axonal versus extra-axonal diffusion by modeling compartment specific tensors,115 as well as methods for modeling free pools of water,118 have been developed but have only recently been applied to


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25 mTBI populations.119 Recent evidence from animal models suggests that measures of nonGaussian diffusion (kurtosis) are increased in the acute injury phase, display an inverse gradient with distance from impact site, and remained significantly elevated longer than more standard DTI scalars.29 Studies that apply similar techniques in human studies will be crucial for resolving questions regarding extra-axonal versus intra-axonal versus total water (cytotoxic and vasogenic edema). Conclusion In summary, DTI has helped reshape our understanding of the neuropathological effects associated with mTBI. Given the heterogeneity and “chaos” inherently associated with clinical mTBI research,45 DTI studies with more homogeneous inclusion criteria (time post-injury, injury severity and past history), larger sample sizes and more sophisticated data acquisition/analyses schemes are critically needed to determine the true utility of this imaging technique for the acute and semi-acute stages of mTBI. Author Disclosure Statement No competing financial interests exist.


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Figure Legends

Journal of Neurotrauma Diffusion Tensor Imaging Findings in Semi-Acute Mild Traumatic Brain Injury (doi: 10.1089/neu.2014.3337) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Page 43 of 58

43

Figure 1: Figure 1 illustrates the number of DTI studies published per year that included acutely

or semi-acutely injured mTBI patients (37 total as of 11/1/13).


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44

Figure 2: This graph illustrates the distribution of anisotropic diffusion findings across a variety of different clinical and experimental factors. Data is presented for the 31 studies that contained independent samples only (see Table 1). For each category, the number of studies reporting increased anisotropic diffusion is depicted in blue, decreased anisotropic diffusion in green, bidirectional (increased and decreased) anisotropic diffusion in orange and null findings in purple.

Journal of Neurotrauma Diffusion Tensor Imaging Findings in Semi-Acute Mild Traumatic Brain Injury (doi: 10.1089/neu.2014.3337) as been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ fro

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45 Table 1: Studies Reporting Decreased Fractional Anisotropy mTBI Control N(Gender) N(Gender)

Time Post Injury

Field Strength

10 (5F)

Diffusion tensor imaging findings and postconcussion symptom reporting six weeks following mild traumatic brain injury.

Neuropsychological outcome and diffusion tensor imaging in complicated versus uncomplicated mild traumatic brain injury.

Diffusion Tensor Imaging Findings in Post-Concussion Syndrome Patients after Mild Traumatic Brain Injury: A Systematic Review.

Diffusion tensor imaging for outcome prediction in mild traumatic brain injury: a TRACK-TBI study.

Diffusion tensor imaging reveals acute subcortical changes after mild blast-induced traumatic brain injury.

Diffusion Tensor Imaging Parameters in Mild Traumatic Brain Injury and Its Correlation with Early Neuropsychological Impairment: A Longitudinal Study.

White Matter Changes in Posttraumatic Stress Disorder Following Mild Traumatic Brain Injury: A Prospective Longitudinal Diffusion Tensor Imaging Study.

Clinical correlates of cerebral diffusion tensor imaging findings in chronic traumatic spinal cord injury.

Diffusion tensor imaging and magnetic resonance spectroscopy in traumatic brain injury: a review of recent literature.

Primary blast traumatic brain injury in the rat: relating diffusion tensor imaging and behavior.

Altered white matter in cocaine-dependent subjects with traumatic brain injury: A diffusion tensor imaging study.

Emotional prosody and diffusion tensor imaging in children after traumatic brain injury.

Diffusion tensor imaging in acute-to-subacute traumatic brain injury: a longitudinal analysis.

Current and future diagnostic tools for traumatic brain injury: CT, conventional MRI, and diffusion tensor imaging.

White matter and reading deficits after pediatric traumatic brain injury: A diffusion tensor imaging study.

A longitudinal evaluation of diffusion kurtosis imaging in patients with mild traumatic brain injury.

Mild traumatic brain injury.

Mild traumatic brain injury.

Diffusion tensor imaging reveals white matter injury in a rat model of repetitive blast-induced traumatic brain injury.

Changes of an injured fornix in a patient with mild traumatic brain injury: diffusion tensor tractography follow-up study.

Advances in imaging explosive blast mild traumatic brain injury.

Diffusion tensor imaging in traumatic optic tract syndrome.

Normobaric hyperoxia does not improve derangements in diffusion tensor imaging found distant from visible contusions following acute traumatic brain injury.

Radiological-pathological correlation of diffusion tensor and magnetization transfer imaging in a closed head traumatic brain injury model.