Resting-State Functional Connectivity Alterations Associated with Six-Month Outcomes in Mild Traumatic Brain Injury

Abstract

Brain lesions are subtle or absent in most patients with mild traumatic brain injury (mTBI) and the standard clinical criteria are not reliable for predicting long-term outcome. This study investigates resting-state functional MRI (rsfMRI) to assess semiacute alterations in brain connectivity and its relationship with outcome measures assessed 6 months after injury. Seventy-five mTBI patients were recruited as part of the prospective multicenter Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) pilot study and compared with matched 47 healthy subjects. Patients were classified following radiological criteria: CT/MRI positive, evidence of lesions; CT/MRI negative, without evidence of brain lesions. rsfMRI data were acquired and then processed using probabilistic independent component analysis. We compared the functional connectivity of the resting-state networks (RSNs) between patients and controls, as well as group differences in the interactions between RSNs, and related both to cognitive and behavioral performance at 6 months post-injury. Alterations were found in the spatial maps of the RSNs between mTBI patients and healthy controls in networks involved in behavioral and cognition processes. These alterations were predictive of mTBI patients' outcomes at 6 months post-injury. Moreover, different patterns of reduced network interactions were found between the CT/MRI positive and CT/MRI negative patients and the control group. These rsfMRI results demonstrate that even mTBI patients not showing brain lesions on conventional CT/MRI scans can have alterations of functional connectivity at the semiacute stage that help explain their outcomes. These results suggest rsfMRI as a sensitive biomarker both for early diagnosis and for prediction of the cognitive and behavioral performance of these patients.

Keywords: TBI; cognitive and behavioral outcome; rsfMRI.

Conflict of interest statement

No competing financial interests exist

Figures

FIG. 1.

Imaging data preprocessing and analysis summary. Color image is available online at www.liebertpub.com/neu

FIG. 2.

Resting-state networks (RSNs) from the independent component analysis (ICA) group decomposition. (a) Frontoparietal right network; (b) primary visual network; (c) superior parietal network; (d) frontoparietal left; (e) default mode network (DMN) posterior part; (f) DMN; (g) occipito-cerebellar network; (h) ventral attentional network; (i) executive control network; (j) salience network; (k) upper somatomotor network; (l) dorsal attentional network; (m) visual network; (n) dorsal and ventral visual stream; (o) orbitofrontal network; (p) cingular opercular network; (q) lower somatomotor network; (r) auditory network; (s) brainstem and cerebellum network; (t) basal ganglia. Color image is available online at www.liebertpub.com/neu

FIG. 3.

Resting-state networks' (RSNs') significant differences between the whole sample of mTBI patients and healthy controls. (a) Default mode network (DMN); (b) executive control network; (c) frontoparietal network; (d) orbitofrontal network; (e) dorsal attentional network; (f) visual network. In blue: reductions in connectivity. In red-yellow: increases in connectivity. Color image is available online at www.liebertpub.com/neu

FIG. 4.

Group comparisons of CT/MRI positive or negative patients versus controls. Left side: (a) orbitofrontal network; (b) default mode network (DMN); (c) executive control network; (d) frontoparietal network; (e) dorsal attentional network. Right side: (a) orbitofrontal network; (b) DMN; (c) salience network; (d) fronto-parietal network; (e) visual network. In blue: reductions in connectivity. In red-yellow: increases in connectivity. Color image is available online at www.liebertpub.com/neu

FIG. 5.

Rivermead Post Concussion Questionnaire versus functional connectivity in the CT/MRI negative mTBI subgroup. (a) Visual network; (b) occipito-cerebellar network; (c) dorsal visual stream; (d) posterior default mode network. In blue: negative correlations with the behavioral test. Scatter plots show individual mean values for connectivity within the significant areas, in relation to the de-meaned results of the behavioral test. Color image is available online at www.liebertpub.com/neu

FIG. 6.

Increases in connectivity related to cognitive measures in the mild traumatic brain injury (mTBI), MRI negative group. Trail Making Test A (TMT-A), CT/MRI positive mTBI: (a) default mode network (DMN); (b) salience network; (c) dorsal attention network. TMTB-A, CT/MRI negative mTBI: orbitofrontal network. California Verbal Learning Test–(CVLT), CT/MRI negative mTBI: occipito-cerebellar network. In red-yellow: positive correlations with the cognitive test. Scatter plots show individual mean values for connectivity within the significant areas in relation to the de-meaned results of the cognitive tests. Color image is available online at www.liebertpub.com/neu

FIG. 7.

Temporal interactions between resting-state networks (RSNs). (a,b) Pairs of networks with reduced functional connectivity in mild traumatic brain injury (mTBI) patients positive/negative versus controls. (c) Negative correlation between a pair of networks and the executive function measure. Color image is available online at www.liebertpub.com/neu