See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/223958859 Structural integrity and postconcussion syndrome in mild traumatic brain injury patients ARTICLE in BRAIN IMAGING AND BEHAVIOR · APRIL 2012 Impact Factor: 4.6 · DOI: 10.1007/s11682-012-9159-2 · Source: PubMed CITATIONS READS 20 34 8 AUTHORS, INCLUDING: Arnaud Messé Mélanie Pélégrini-Issac 29 PUBLICATIONS 234 CITATIONS 90 PUBLICATIONS 2,240 CITATIONS University Medical Center Hamburg - Eppe… SEE PROFILE Pierre and Marie Curie University - Paris 6 SEE PROFILE Michelle Montreuil Richard Levy 64 PUBLICATIONS 248 CITATIONS 129 PUBLICATIONS 6,590 CITATIONS Université de Vincennes - Paris 8 SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, letting you access and read them immediately. Hôpital Saint-Antoine (Hôpitaux Universitai… SEE PROFILE Available from: Arnaud Messé Retrieved on: 04 February 2016 Structural integrity and postconcussion syndrome in mild traumatic brain injury patients Arnaud Messé, Sophie Caplain, Mélanie Pélégrini-Issac, Sophie Blancho, Michèle Montreuil, Richard Lévy, Stéphane Lehéricy, et al. Brain Imaging and Behavior ISSN 1931-7557 Volume 6 Number 2 Brain Imaging and Behavior (2012) 6:283-292 DOI 10.1007/s11682-012-9159-2 1 23 Your article is protected by copyright and all rights are held exclusively by Springer Science+Business Media, LLC. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your work, please use the accepted author’s version for posting to your own website or your institution’s repository. You may further deposit the accepted author’s version on a funder’s repository at a funder’s request, provided it is not made publicly available until 12 months after publication. 1 23 Author's personal copy Brain Imaging and Behavior (2012) 6:283–292 DOI 10.1007/s11682-012-9159-2 Structural integrity and postconcussion syndrome in mild traumatic brain injury patients Arnaud Messé · Sophie Caplain · Mélanie Pélégrini-Issac · Sophie Blancho · Michèle Montreuil · Richard Lévy · Stéphane Lehéricy · Habib Benali Published online: 4 April 2012 © Springer Science+Business Media, LLC 2012 Abstract The presence of a postconcussion syndrome (PCS) induces substantial socio-professional troubles in mild traumatic brain injury (mTBI) patients. Although the exact origin of these disorders is not known, they may be the consequence of diffuse axonal injury (DAI) impacting structural integrity. In the present study, we compared structural integrity at the subacute and late stages after mTBI and in case of PCS, using diffusionweighted imaging (DWI). Fifty-three mTBI patients were investigated and compared with 40 healthy controls. All patients underwent a DWI examination at the subacute (8–21 days) and late (6 months) phases after This study was initiated by the IRME (Institut pour la Recherche sur la Moelle Epinière et l’Encéphale) and supported by a grant from the GMF (Garantie Mutuelle des Fonctionnaires). injury. MTBI patients with PCS were detected at the subacute phase using the ICD-10 classification. Groupwise differences in structural integrity were investigated using Tract-Based Spatial Statistics (TBSS). A loss of structural integrity was found in mTBI patients at the subacute phase but partially resolved over time. Moreover, we observed that mTBI patients with PCS had greater and wider structural impairment than patients without PCS. These damages persisted over time for PCS patients, while mTBI patients without PCS partly recovered. In conclusion, our results strengthen the relationship between structural integrity and PCS. Keywords Mild TBI · Postconcussion syndrome · Structural integrity · Diffuse axonal injury Electronic supplementary material The online version of this article (doi:10.1007/s11682-012-9159-2) contains supplementary material, which is available to authorized users. A. Messé (B) · M. Pélégrini-Issac · H. Benali UMRS 678, Laboratoire d’Imagerie Fonctionnelle, Inserm, UPMC Univ Paris 06, Paris 75634, France e-mail: Arnaud.Messe@imed.jussieu.fr R. Lévy · S. Lehéricy UMRS 975, CNRS UMR 7225, CRICM, Groupe Hospitalier Pitié-Salpêtrière, Inserm, UPMC Univ Paris 06, Paris 75013, France A. Messé · M. Pélégrini-Issac · S. Lehéricy · H. Benali DSV/I2 BM/NeuroSpin, IFR49, Univ Paris 11, Bât 145, Gif-sur-Yvette 91191, France R. Lévy Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris, Paris 75012, France S. Caplain · M. Montreuil EA 2027, Psychopathologie et Neuropsychologie, Vincennes-Saint-Denis Univ Paris 08, Saint-Denis 93526, France S. Lehéricy CENIR, Center for Neuroimaging Research, CHU Pitié-Salpêtrière, UPMC Univ Paris 06, Paris 75013, France S. Blancho Institut pour la Recherche sur la Moelle Epinière et l’Encéphale, Paris 75015, France H. Benali MIC/UNF, Université de Montréal, H3W 1W5 Montréal, Canada Author's personal copy 284 Introduction Mild traumatic brain injury (mTBI) represents about 70 to 90% of all TBI types (Carroll et al. 2004; Langlois et al. 2006; Tiret et al. 1990). Mild TBI can induce long-term functional disorders known as the postconcussion syndrome (PCS), which is characterized by the presence of subjective complaints (Dikmen et al. 1986; Iverson 2005). In about 10 to 20% of mTBI patients, PCS-related complaints last several months to years (Stålnacke et al. 2005; Willer and Leddy 2006) and induce substantial socio-professional troubles (Von Wild 2008). Therefore, mTBI is considered as a public health problem (Kraus et al. 1994; Hall et al. 2005). Thus, it is fundamental to find objective marker(s) (especially biophysiological) of this syndrome (Bazarian 2010). The question of the origin of PCS has been heavily debated for many years (McCrea 2008), the subjectivity of the complaints making its assessment difficult (Bigler 2008). Although the exact origin of PCS-related cognitive and neurobehavioral disorders is still unknown, they may be partially the consequence of diffuse axonal injury (DAI), which impacts structural integrity (Parizel et al. 2005; Bigler and Bazarian 2010; Niogi and Mukherjee 2010). Structural integrity is the science of the margin between intact (safety) and damaged (disaster) anatomical brain architecture. Which regions are predominantly affected in mTBI with associated PCS is unclear however. Structural integrity associated with mTBI has been extensively studied and revisited in recent years thanks to diffusion-weighted imaging (DWI) (Bigler and Bazarian 2010). DWI is a sensitive technique that gives access in vivo to the structural integrity of the white matter via the displacement of water molecules (Johansen-Berg and Rushworth 2009). DWI provides information on brain white matter, such as fractional anisotropy (FA), mean, axial and radial diffusivity (MD, AD, and RD, respectively), and is therefore a promising tool for studying DAI (Arfanakis et al. 2002; Niogi and Mukherjee 2010), see Shenton et al., this issue. Other alternatives could be employed to investigate the structural integrity such as MR spectroscopy or even post-mortem immunohistochemical markers (Belanger et al. 2007; Bigler 2010), see Lin et al., this issue. Recently, some histopathological studies have related AD and RD to axonal and myelin integrity, respectively, while FA seems to characterize more complex biophysiological processes, especially axonal density (Song et al. 2003; Budde et al. 2007; Bigler and Bazarian 2010; Concha et al. 2010). While conventional structural (i.e. T1 -weighted) MR imaging appears as “normal”, DWI data has shown Brain Imaging and Behavior (2012) 6:283–292 diffuse brain white matter lesions (Nakayama et al. 2006; Scheid et al. 2006; Bazarian et al. 2007). However, it is still ambiguous how these structural patterns evolve over time in mTBI patients. In Mayer et al. (2010), the authors found a significant increase in fractional anisotropy and decrease in radial diffusivity in several left hemisphere tracts, and longitudinal data demonstrated a partial normalization of these scalars after 3 to 5 months post-injury. However, other studies showed mixed findings (Arfanakis et al. 2002; Inglese et al. 2005; Bendlin et al. 2008; Kinnunen et al. 2011). More recently, some studies have shown that structural integrity as measured by DWI was correlated with neuropsychology, for a review see Fitzgerald and Crosson (2011) and Shenton et al., this issue. Interestingly, white matter properties (mainly FA and MD) were found to be correlated to subjective complaints (Bazarian et al. 2007; Messé et al. 2010; Smits et al. 2011). Such findings suggest that symptoms have organical origins and that structural integrity could be a biomarker of the PCS (Messé et al. 2010). However, these results need to be replicated and confirmed from other studies with larger sample size. In the present study, we compared structural integrity at the subacute and late stage after mTBI and in case of presence (or absence) of PCS. Brain structural integrity was assessed using diffusion imaging. We hypothesized a loss of structural integrity in mTBI patients (with or without PCS) and that these damages resolved in time. When splitting mTBI patients according to the presence or absence of PCS, we expected that most of the loss of structural integrity would be observed in mTBI patients with PCS. Moreover, we tested the hypothesis that MD was an interesting candidate biomarker of PCS as previously observed in the literature (Messé et al. 2010). Materials and methods Participants This study was approved by the local Ethics Committee of the Pitié-Salpêtrière Hospital (Paris, France), and informed consent was obtained for all subjects, at the time of writing the recruitment was still open. Patients were recruited from the Emergency Department of Bicêtre Hospital (Kremlin-Bicêtre, France) and Bichat Hospital (Paris, France). Inclusion criteria of mTBI were defined according to the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine (Kay et al. 1993). Trauma-induced physiological disruption of Author's personal copy Brain Imaging and Behavior (2012) 6:283–292 brain function manifested by at least one of the following signs: loss of consciousness of less than 30 min, a Glasgow Coma Scale (GCS) score between 13 and 15 and/or post-traumatic amnesia no greater than 24 h and/or any alteration in mental state at the time of the injury (confusion, disorientation...), and/or focal neurological deficit possibly transient. Additionally, noninclusion criteria of mTBI were defined as: history of chronic alcohol or drug abuse, previous TBI, contraindications to MRI, intubation and/or presence of a skull fracture and administration of sedatives on arrival in the emergency department, spinal cord injury, neurological signs or multiple disabilities (including at least one life-threatening injury associated), head injury following autolysis, patients with psychiatric or psychological disabilities that may interfere with the monitoring and/or evaluation, psychotropic medication at the time of TBI, history of hospitalization especially in psychiatry and/or arrest for psychological reasons, pre-existing neurological condition. Exclusion criteria were the presence of a major depressive syndrome according to the DSM-IV (1994), patients not participating fully in the procedure, MRI artefacts and/or poor image quality (see next section). Healthy volunteers with neither known history of neurological or psychiatric disease nor any contraindications to MRI, and neither inclusion nor exclusion criteria, were also recruited. Procedure All patients underwent an MRI investigation and clinical tests at the subacute (8–21 days, t1 ) and late (6 months, t2 ) phases after injury. Volunteers had only one MRI investigation and clinical tests. PCS was established at t1 based on the Rivermead Postconcussion Symptoms Questionnaire (RPSQ) (King et al. 1995) and the ICD-10 criteria (ICD-10 1993). Patients with at least one postconcussion symptom (even rated as mild) in each of the following categories: behavioral and emotional symptoms (irritability, depression, problems tolerating stress/emotion/alcohol, reduced spontaneous activity), subjective cognitive impairment (forgetfulness, poor concentration/memory) and somatic complaints (fatigue, headache, sensitivity to noise, sleep/vision disturbance, dizziness) were classified as having a PCS (PCS+, PCS− otherwise). Subjects rated the severity of each symptom within the last 24 h from 0 (no or not more symptoms within the last 24 h) to 4 (much more severe symptoms within the last 24 h). Reliability and validity have been demonstrated in the context of mTBI (Crawford et al. 1996; Eyres et al. 2005). Demographic indices were also em- 285 ployed to characterize participants, such as age, gender and socio-cultural level (SCL).1 MRI protocol The MRI protocol consisted of structural and functional images acquired on a 3T Siemens Trio TIM system (CENIR, Paris, France), here we only focused on DWI data. For structural details, we used an axial echo-planar DWI acquisition (FOV 240×240 mm2 ; 56 contiguous slices; TR/TE = 10,000/87 ms; voxel size 2 mm3 isotropic; no average). One non-weighted image with b = 0 s/mm2 was acquired, and diffusion-weighted images with b = 1,000 s/mm2 were also acquired in 50 non-collinear gradient directions. By visual inspection, DWI data with misplaced field-of-view not covering the whole brain, artefacts due to MR instability or any technical problem (e.g. sequence stopped before ending), were not considered in the analysis. Statistical analysis Participant characteristics Classical statistical inference was used to test differences between controls, mTBI and PCS−/PCS+ patients at p < 0.05 significance, with Student’s t test for continuous variables (age, GCS and the number of symptoms), Fisher’s exact test for categorical variables (gender) and Mann-Whitney U test for ordinal variables (SCL). DWI data Structural integrity was investigated in a groupwise approach between all mTBI patients, PCS− patients, PCS+ patients and controls using Tract-Based Spatial Statistics (TBSS) (Smith et al. 2006), part of the FMRIB Software Library (FSL)2 (Woolrich et al. 2009). First, DWI data were corrected for head motion and Eddy current artefacts using linear image registration. FA, MD, AD, and RD maps were computed by fitting a tensor model to the DWI data and the brain mask was extracted based on the unweighted image b = 0 using the Brain Extraction Toolbox (BET) (Smith 2002). The FA map of each participant was then aligned to the Montreal Neurological Institute (MNI) standard spaceusing nonlinear warping. The FA maps were 1 The socio-cultural level is function of the number of years of education, ranging from 1 (primary school or less) to 5 (university degree), through 3 (Bachelor) (GREFEX 2001). 2 FSL, FMRIB, Oxford, UK: www.fmrib.ox.ac.uk/fsl/. Author's personal copy 286 Brain Imaging and Behavior (2012) 6:283–292 Table 1 Characteristics of controls and mTBI patients Age, mean (SD) Gender, ratio (F/M) SCL, mean (SD) GCS, mean (SD) RPSQ, mean (SD) Controls (n = 40) mTBI (n = 53) 36.3 (12.5) 12/28 3.6 (1.1) – 1.9 (1.7) 35.5 (11.0) 18/35 3.6 (1.2) 15 (0.2) 6.5 (4.8) C/mTBI p 0.76 0.82 0.93 – <0.001 d score (which is simply the difference between the two group means divided by the standard deviation of the data). Groupwise differences in participant characteristics and structural integrity were assessed using the following comparisons: mTBI patients versus controls, PCS−/PCS+ patients versus controls, and PCS− versus PCS+ patients, at t1 and t2 phases. C: controls; F: female; GCS: Glasgow Coma Scale; M: male; RPSQ: Rivermead Postconcussion Symptoms Questionnaire; SCL: socio-cultural level; SD: standard deviation Bold means significant difference of the given measure, i.e. p < 0.05 Results averaged and thinned to produce a group mean FA skeleton, which is assumed to correspond to the centers of all white matter tracts common to the group. FA values for each individual subject were then projected onto this group mean skeleton. For MD, AD and RD maps, values for each individual subject were projected to the MNI space using the transformation previously caculated for the FA map. Permutation-based non-parametric testing was used to assess significant group differences, controlled for age, gender and SCL, enhanced using Threshold-Free Cluster Enhancement (TFCE) (Smith and Nichols 2009) and corrected for multiple comparisons using the Family-Wise Error (FWE) rate. Anatomical labelling of the tracts where significant group differences were found was performed using the Johns Hopkins University DTI-based white-matter atlases (Mori et al. 2005). Additionally, the strength of the group differences (i.e. effect size) was assessed using Cohen’s A total of 85 patients with mTBI were initially recruited (61 men; mean age± standard deviation (SD): 33.6±11.3 years). Of these, 20 did not fullfill the procedure and 12 presented poor image quality and were excluded, resulting in a total of 53 mTBI patients who were finally included and examined. Additionally, 42 healthy volunteers were recruited, 2 were rejected due to poor MRI quality. There was no difference between mTBI patients and controls for age, gender, and SCL. However, we observed a much larger number of symptoms in mTBI patients than in controls (Table 1). The TBSS analysis showed several brain regions where diffusion properties were significantly different in mTBI patients compared to controls. MTBI patients had lower FA values than controls in widespread regions, mainly involving the corpus callosum, the cerebellar peduncle, the internal and external capsules, the corona radiata and the thalamic radiation, the sagittal stratum, the fornix, and the superior longitudinal fasciculus (see supplementary Table 5 and Fig. 4, top row). Table 2 Regions of significant MD decrease in mTBI patients at t1 and t2 phases compared to controls Clusters are significant at p < 0.05, corrected for multiple comparisons. Size, p and d corresponds to the number of voxels, the average p-corrected value and Cohen’s d value within atlas regions, respectively L: left; R: right Tracts Body of corpus callosum Splenium of corpus callosum Cerebral peduncle Anterior limb of internal capsule Posterior limb of internal capsule Retrolenticular part of internal capsule Superior corona radiata Posterior corona radiata Posterior thalamic radiation Sagittal stratum External capsule Cingulum Fornix / Stria terminalis Superior longitudinal fasciculus Tapetum Side R R R R R R L R L R R R R R R t1 phase t2 phase Size p d Size p d 1043 390 0.025 0.035 −1.02 −0.72 44 193 13 584 395 72 29 0.029 0.031 0.036 0.026 0.031 0.044 0.037 −0.72 −0.69 −0.53 −0.93 −0.82 −0.80 −0.73 164 0.034 −0.76 877 1125 130 46 461 233 555 593 118 650 295 158 220 0.011 0.013 0.028 0.013 0.019 0.018 0.009 0.007 0.019 0.010 0.026 0.031 0.024 −1.00 −1.03 −1.18 −0.68 −0.86 −0.91 −0.83 −0.96 −0.90 −0.98 −0.99 −0.81 −0.75 15 0.030 −0.52 761 13 0.025 0.038 −0.78 −0.52 58 935 29 0.020 0.007 0.005 −0.67 −0.98 −0.84 Author's personal copy Brain Imaging and Behavior (2012) 6:283–292 287 Table 3 PCS− and PCS+ patients characteristics Age, mean (SD) Gender, ratio (F/M) SCL, mean (SD) GCS, mean (SD) RPSQ, mean (SD) PCS− (n = 31) PCS+ (n = 22) PCS−/PCS+ p C/PCS− p 33.0 (11.5) 7/24 3.8 (1.2) 14.9 (0.2) 3.2 (2.6) 39.2 (9.4) 11/11 3.4 (1.3) 15 (0.0) 11.2 (3.0) 0.04 0.03 0.26 0.23 <0.001 0.25 0.48 0.48 – 0.01 C/PCS+ p 0.35 0.12 0.48 – <0.001 C: controls; F: female; GCS: Glasgow Coma Scale; M: male; RPSQ: Rivermead Postconcussion Symptoms Questionnaire; SCL: socio-cultural level; SD: standard deviation Bold means significant difference of the given measure, i.e. p < 0.05 Fig. 1 Controls versus PCS− patients: results of the TBSS analysis, overlaid on axial views of the mean FA image (neurological convention). Blue, red and pink color represent significant decrease in diffusion scalar in PCS− patients at t1 , t2 and both t1 and t2 , respectively, while violet, yellow and white color represent significant increase in PCS− patients at t1 , t2 and both t1 and t2 respectively, compared to controls. FA, MD, AD and RD significant differences are displayed from top to bottom row. Clusters are significant at p < 0.05, corrected for multiple comparisons MTBI patients presented similar patterns of regions with higher MD and RD values than controls mainly within regions of lower FA with more distal regions (e.g. the corpus callosum and the superior longitudinal fasciculus), while no significant differences were found in AD values between groups (Table 2 and Fig. 4). No difference was found between t1 and t2 phases in mTBI patients, however we observed that in regions with significant differences in diffusion properties between mTBI and controls, differences tended to decrease at t2 compared to t1 . Twenty-two PCS+ and 31 PCS− were identified on the basis of their symptoms at t1 . No significant difference was found between PCS+ and PCS− patients for SCL and GCS scores,3 while age, the number of RPSQ symptoms, and the proportion of females were significantly higher in PCS+ than in PCS− patients. We observed also that the number of symptoms was significantly higher for PCS− patients and for PCS+ patients compared to controls (Table 3). TBSS showed several regions where diffusion measures were significantly different in PCS− and PCS+ mTBI patients compared to controls (Figs. 1 and 2). 3 There were only two patients in PCS− group with GCS = 14, all other GCS scores were equal to 15. Author's personal copy 288 Brain Imaging and Behavior (2012) 6:283–292 Fig. 2 Controls versus PCS+ patients: results of the TBSS analysis, overlaid on axial views of the mean FA image (neurological convention, with the same color code as in Fig. 1). Results for FA, MD, AD and RD scalars are shown from top to bottom row. Clusters are significant at p < 0.05, corrected for multiple comparisons The pattern of regions with significant differences in terms of FA and RD when comparing PCS− with controls was similar to that found when comparing all mTBI patients with controls at t1 and t2 (see Fig. 4). Note that we observed more (resp. less) regions with significant differences in FA (resp. RD) values in PCS− patients compared to controls at t2 . Only small parts of the splenium of the corpus callosum and the right superior longitudinal fasciculus had higher MD values for PCS− than for controls at t2 . No statistical difference was found in AD values. PCS+ patients had widespread regions (primarily involving longitudinal fasciculi and the corpus callosum) with abnormal MD, AD, and RD values compared to controls at both t1 and t2 Table 4 Changes in structural integrity after mTBI with or without PCS, compared to healthy condition PCS− FA MD AD RD PCS+ Subacute Late Subacute Late ց ↔ ↔ ր ց ↔ (ր) ↔ ↔ (ր) ↔ ր ր ր ց ր (↔) ր (↔) ր (↔) Arrows within brackets stand for some tendency (Table 4). The regions with significant lower FA values at t2 in PCS+ patients compared to controls involved mainly the superior longitudinal and fronto-occipital fasciculus and the splenium, in the right hemisphere. Significant structural differences were found between PCS+ and PCS− groups at t1 and less at t2 for the MD and AD measures, these involved primarily the corpus callosum, the longitudinal fasciculus and the internal capsules (Fig. 3). Discussion In this study, compared with controls, mTBI patients presented decreased (resp. increased) fractional anisotropy (resp. mean diffusivity, axial and radial diffusivity) values in association, commissural and projection white matter fiber tracts and these changes evolved over time. When comparing mTBI patients on the basis of their complaints, PCS+ patients had greater and wider impaired brain regions (i.e. with diffusion measures significantly different) than PCS− patients, at the subacute and late phases. Moreover, significant difference was found between PCS+ and PCS− patients in MD and AD values. These results support the Author's personal copy Brain Imaging and Behavior (2012) 6:283–292 289 Fig. 3 PCS− versus PCS+ patients: results of the TBSS analysis, overlaid on axial views of the mean FA image (neurological convention, with the same color code as in Fig. 1). Results for FA, MD, AD and RD scalars are shown from top to bottom row. Clusters are significant at p < 0.05, corrected for multiple comparisons hypothesis that TBI-induced lasting damages in white matter fiber bundles could explain the pathological substrate of PCS in mTBI, at least when considering the ICD-10 definition of the PCS. Diffuse axonal injury associated with traumatic brain injury has been demonstrated in oversized studies. Most of them have used DWI to quantify structural integrity in mTBI patients and related DAI (Arfanakis et al. 2002; Huisman et al. 2004; Inglese et al. 2005; Salmond et al. 2006; Kraus et al. 2007; Rutgers et al. 2008; Lipton et al. 2009; Levin et al. 2010; Mayer et al. 2010), see Bigler and Bazarian (2010) and Niogi and Mukherjee (2010) for excellent reviews. Here we found a loss of structural integrity in all mTBI patients, whether they were classified as having a PCS or not, at the subacute phase of injury and PCS− patients partly recovered at late phase while PCS+ patients did not. The mechanism observed here from the diffusion scalars seems to be related to the diffuse axonal injury process as suggested in histopathological studies (Budde et al. 2007; Concha et al. 2010). Decrease in FA and increase in mean and radial diffusivity values characterize an axonal loss accompanied by an increase in axonal circumference and extra-axonal space (Concha et al. 2010), which may correspond to the disruption of axons caused by the traumatic shearing forces that occur during the injury. Our results are similar to those from most previous studies, which were mainly cross-sectional. MTBI is inherently heterogeneous, the patients selection criteria, demographic characteristics, injury origins/location, or even imaging techniques and analyses employed, could induce mixed findings. Moreover, mTBI patients behave differently in response to injury: some of them recover in a few days post-injury while others fail to overcome the trauma depending on their symptoms. Some recent specific researches on PCS have demonstrated to some extent a relationship between this syndrome and structural integrity (Fitzgerald and Crosson 2011). DWI scalars such as FA and MD at acute phase after injury were correlated with average postconcussion symptoms severity score (Bazarian et al. 2007; Smits et al. 2011). PCS after mTBI remains difficult to predict at the subacute phase, whether clinically or using MRI, however, a subacute and appropriate care could be very helpful for patient’s recovery. Here, we detected the presence of PCS in mTBI patients based on their symptoms identified by complaints at the acute phase after injury (within four weeks postinjury) and we specifically investigated brain lesions Author's personal copy 290 associated with that syndrome longitudinally. We observed that mTBI patients with PCS had greater and wider structural damages than mTBI patients without PCS, moreover these damages persist at late phase. We observed likewise a resorption of DAI damages at late phase for mTBI patients without PCS (see Table 4, for a summary of the diffusion mechanisms observed). Our results are consistent with our previous study (Messé et al. 2010) and provide chronic consequences on structural integrity. Moreover, we observed that even if the patients had a mild TBI, i.e. having mainly a GCS score equal to 15, widespread DAI were detected. Our study has some limitations. The main limitation was the criteria defining the PCS in mTBI patients, indeed no consensus exists in the definition of PCS (Wilde et al. 2010). We used the ICD10 classification (ICD-10 1993) as in our previous study (Messé et al. 2010), which is less restrictive than the DSM-IV criteria in that it does not include affective and personality changes, and therefore induces higher PCS prevalence (Boake et al. 2005). The DSM-IV criteria are based on the symptoms present at the late phase after the injury (at least after 3 months). These chronic symptoms are potentially psychogenic while acute symptoms could be physiogenic (Yeates and Taylor 2005). It would be of great interest to examine to which extent PCS definitions differ and how this affects structural integrity findings. Last, mTBI patients were simply classified as with or without PCS. The RPSQ quantifies symptoms severity, as in Bazarian et al. (2007) and Smits et al. (2011); it would be interesting to specifically correlate this severity to structural integrity. Conclusions A more widespread loss of structural integrity was found in mTBI patients with PCS than in mTBI patients without PCS. Moreover, these damages persist over time for PCS patients, while mTBI patients without PCS partly recovered. The results strengthen the relationship between structural integrity and PCS. Further investigation remains to be conducted to refine PCS criteria (potentially including MRI biomarkers) and specify how much the delay after the trauma influences symptom severity and origin. We are currently trying to address the issue of a full PCS characterization by coupling MRI modalities and clinical and psychological evaluation. Acknowledgements We would like to thank all study participants. The authors are grateful to the MRI acquisition team (CENIR, Paris, France) for capital support. Brain Imaging and Behavior (2012) 6:283–292 References Arfanakis, K., Haughton, V. M., Carew, J. D., Rogers, B. P., Dempsey, R. J., & Meyerand, M. E. (2002). Diffusion tensor MR imaging in diffuse axonal injury. American Journal of Neuroradiology, 23, 794–802. Bazarian, J. (2010). Diagnosis of mild traumatic brain injury after a concussion. Journal of Head Trauma Rehabilitation, 25, 225–227. Bazarian, J., Zhong, J., Blyth, B., Zhu, T., Kavcic, V., & Peterson, D. (2007). 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