Functional Connectivity Patterns Following Mild Traumatic Brain Injury and the Association With Longitudinal Cognitive Function

Abstract

Functional magnetic resonance imaging (fMRI) has revealed subtle neuroplastic changes in brain networks following mild traumatic brain injury (mTBI), even when standard clinical imaging fails to detect abnormalities. However, prior findings have been inconsistent, in part due to methodological differences and high researcher degrees of freedom in region-based analyses, which often rely on predefined hypotheses and overlook complex, distributed connectivity patterns. Here, we apply an unbiased, data-driven multi-voxel pattern analysis (MVPA) to examine whole-brain functional connectivity differences in a large cohort of individuals with acute mTBI. Unlike conventional statistical approaches, MVPA enables a data-driven analysis of brain-wide connectivity patterns without requiring prior assumptions about the location or nature of abnormalities, allowing for the identification of the most informative features. This approach provides an exploratory characterization of whole-brain functional connectivity patterns and their relationship with cognitive recovery, offering new insights into the neural mechanisms underlying post-injury outcomes. A total of 265 adults (87 women) between 18 and 83 years old with Glasgow Coma Scale (GCS) scores of 13–15 were included in this analysis. Two replicate samples (n = 165, n = 155), with similar demographic characteristics, were also included. Data were collected as part of the prospective multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI). The goal of this study was to assess whole-brain functional connectivity patterns using fc-MVPA and post hoc seed-to-voxel analyses in a large, well-characterized sample to determine if changes in functional connectivity can differentiate subacute mTBI (within 2 weeks of injury) from a matched group of orthopedic control subjects (n = 49). Additionally, we aimed to investigate whether these connectivity patterns were linked to cognitive performance at 2 weeks, 6 months, and 12 months post-injury to better understand cognitive trajectories and recovery over time in individuals with mTBI. Voxel-to-voxel functional connectivity across the entire connectome revealed significant differences between TBI and no TBI in the functional connectivity patterns of 8 clusters (p-voxel < 0.001, FEW cluster-level p < 0.05) (k > 40, Fmax = 15.36), including right occipital cortex, anterior cingulate gyrus, inferior and middle temporal gyrus, right thalamus, left cerebellum, and the bilateral frontal pole. These clusters belong mainly to the visual network (VIS), frontoparietal network (FPN), default mode network (DMN) and limbic network (LIM). Post hoc characterization of each significant cluster revealed by MVPA using seed-to-voxel analysis showed a mixed pattern of connectivity between relevant networks and subcortico-cortical connections. After connectivity characterization, visual-motor skills assessed with Trail Making Test (TMT) A were significantly associated with the increased anticorrelation between the inferior temporal cortex and the bilateral occipital pole (FPN-VIS connectivity), along with decreased anticorrelations between the cerebellum and extensive areas of the somatomotor network (SMN) over 12 months post injury. Additionally, hypoconnectivity between the frontal pole (LIM) and anterior cingulate gyrus (salience network [SAL]) was associated with better executive functions performance measured by TMT-B over 12 months post-mTBI. In our study examining neuroplastic changes following TBI across the entire voxel-to-voxel functional connectome, we identified significant differences in the functional connectivity patterns of several regions known to be particularly vulnerable to injury mechanisms. Our findings highlight the complex and compensatory nature of brain network alterations after mTBI, suggesting both detrimental and adaptive changes in connectivity that affect cognitive functions. Consequently, our study provides novel evidence that specific brain networks and regions are particularly susceptible to functional connectivity changes during the acute stages of mTBI, which are related to cognitive recovery post-injury.