Disrupted brain functional hub and causal connectivity in acute mild traumatic brain injury

Introduction

Traumatic brain injury (TBI) is a traumatic brain structural injury or an injury in which other changes in brain function caused by external forces occur; TBI is a major reason for sustained disability and morbidity, both in military populations and civilians [1]. Mild TBI (mTBI) is the most common type of traumatic brain injury, representing 80%–90% of TBI cases [2]. Many mTBI patients may develop a wide range of cognitive deficits, such as deficits in executive function, attention, and working memory [3, 4]. Although most mTBI patients recover quickly, approximately 10%-15% of patients have disabling problems that persist for a long time [5]. However, to date, no obvious structural damage has been identified in mTBI patients when using traditional brain imaging techniques (i.e., computed tomography (CT) and magnetic resonance imaging (MRI)) [6]. Therefore, the cognitive problems of many mTBI patients may be underrated and thus have a substantial impact on the patients’ lives and social interactions. Nonetheless, the pathophysiologic mechanisms of mTBI that cause the disorder to be persistent remain poorly understood.

Previous neuroimaging studies using positron emission tomography (PET), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) have investigated the neuropathophysiological mechanisms implicated in subacute and chronic mTBI patients [7–9]. Resting-state fMRI (rs-fMRI), which reflects brain activity while an individual is resting and not performing a specific task, may reveal damage to cognitive function caused by mTBI [10]. Using rs-fMRI, multiple resting-state brain intrinsic networks relevant to the neural mechanisms of mTBI have been demonstrated, such as the default mode network (DMN) [11, 12], executive control network (ECN) [13], and motor network [14]. However, these results were variable due to the application of different approaches to rs-fMRI data analysis and the selection of pre- and post-processing procedures and heterogeneous samples. Mayer et al. implied that there was decreased functional connectivity (FC) within the DMN in chronic mTBI patients using seed-based rs-fMRI analysis [15]. Through independent component analysis (ICA), Palacios et al. found that mTBI patients in the subacute stage showed reduced connectivity in the ECN, the frontal nodes of the DMN and the parietal areas of the dorsal attentional network, as well as an increase in connectivity in the visual network [10]. Through the fractional amplitude of low-frequency fluctuations (fALFF), Madhavan et al. observed decreased fALFF in the motor, language, visual and salience networks for patients with higher symptom severity scores [16]. Heterogeneity among mTBI populations may lead to changes in network status. Based on these latest theories and observations, we speculate that the pathophysiological basis of acute mTBI may be due to disrupted brain function and network hubs.

The latest rs-fMRI studies identified abnormalities in the prefrontal cortex (PFC) associated with mTBI-related cognitive deficits, such as deficits in executive function, attention and working memory [17–20]. The PFC is a collection of interconnected new cortical regions that sends and receives projections from cortical motor systems, sensory systems, and many subcortical structures. The PFC helps to improve cognitive function and has been shown to be an important brain structure for performing executive functions [21]. Previous neuroimaging studies have confirmed the involvement of the PFC in the regulation and adaption of cognitive impairment after mTBI [22, 23]. Additionally considering the theory that the PFC is vulnerable to neural contusion, the PFC is considered a key region involved in mTBI. Therefore, exploring the role of the PFC in the brain functional network hubs of mTBI patients will provide valuable insights into the neural mechanisms of mTBI.

The ICA and seed-based FC approaches have been proved extremely useful in exploring FC patterns for specific components of interest. However, few studies have investigated the acute mTBI-related changes of whole-brain FC pattern or large-scale brain network. Degree centrality (DC) is a voxel-wise data-driven method for quantifying the importance of each node in a brain network [24]. This graph theory based on network analysis can evaluate the centrality of a network without selecting interested nodes or networks in advance. In addition, in order to examine the directional connectivity network involved in acute mTBI, Granger causality analysis (GCA) will be applied to evaluate the directional effects between simultaneously recorded time series. GCA allows the directional connections between different brain regions to be studied and the changes in brain networks to be dynamically observed, and GCA has been used to reveal causal relationships among brain regions in individuals with various diseases, such as autism, schizophrenia, Alzheimer’s disease (AD), and presbycusis [25–28]. However, it remains to be determined whether such DC and causal connection abnormalities can be observed at the early stages of mTBI.

Thus, in the present study, in order to unravel the details of the network hub and causal connectivity of brain function in mTBI patients in the acute stage, we used DC to quantify the importance of each node in the brain network in patients with acute mTBI, based on the strength of its connection to all the other voxels and then used GCA to analyze the causal connections and understand the directional aspects of these changes. We further aimed to determine whether DC and causal connection abnormalities are associated with cognitive dysfunction performance in acute mTBI patients. We hypothesized that (1) the intrinsic disconnection pattern of PFC plays a pivotal role in the brain functional network of mTBI patients at the acute stage. (2) DC and causal connection abnormalities would be associated with cognitive dysfunction performance in mTBI patients at the acute stage.

Results

Discussion

This is the first study to use both DC and GCA approaches to explore intrinsic brain functional hubs and causal connectivity in mTBI patients at the acute stage. Using DC analysis, we found significantly decreased network centrality within the left MFG region in acute mTBI patients than in HCs. Using the GCA algorithm, we employed the left MFG as a seed to examine its causal effect with the whole brain. Specifically, the left MFG showed decreased causal connectivity with several regions, including the prefrontal, temporal and cingulate cortex. In addition, the left ACC showed significantly increased causal connectivity to the left MFG. Of note, the DC abnormalities in the left MFG and the disrupted causal connectivity between left ACC and left MFG were significantly correlated with cognitive function performance in mTBI patients at the acute stage. The current study could provide deeper insights into this issue and further confirm the concept that the acute mTBI is a pathophysiological process related to aberrant brain connectivity.

DC is the most direct measure to characterize node centrality in a network analysis. The higher the degree centrality a network node has, the more important the node is in the network. Numerous studies over the past century have confirmed the idea that the human brain network consists of neurons connected in complex patterns that support different cognition functions [29]. Our findings showed significantly decreased DC in the left MFG region of mTBI patients than in that of HCs, suggesting that the left MFG is the main brain functional hub affected by acute mTBI, which is consistent with the hypothesis that the dysconnectivity pattern of the PFC is involved in acute mTBI. However, only unilateral DC abnormalities were found in our study. A possible reason for this result is that the locations of the forces that caused head trauma in the patients included in this study were not completely consistent and need to be further explored. PFC is considered a key area by many TBI studies, which shows that the PFC is associated with many aspects of posttraumatic symptoms and cognitive impairment in individuals with mTBI [30, 22]. Harm et al. demonstrated significantly lower activation levels within the medial PFC in patients with mTBI in the subacute stage postinjury compared to HCs by using GLM analysis [17]. Moreover, Sullivan and colleagues found that chronic blast-related mTBI patients showed higher deactivation levels within the left dorsomedial PFC [13].

In the current study, we observed that decreased DC in the left MFG region was positively associated with the total MoCA score and attention score among patients with mTBI in the acute stage. These findings were consistent with the role of the PFC in the development of persistent cognitive and emotional impairment after a concussion. Consistent with this notion, previous studies have also reported functional alterations within the PFC region, both in moderate/severe TBI and in mild TBI, and such changes have been linked to cognitive performance [31–33]. Moreover, there is also evidence of structural and neurochemical abnormalities in the PFG and a relationship between the structural and neurochemical changes and cognitive performance [21]. Dall et al. demonstrated increased thickness within the PFC regions and weak correlations between the amount of PFC thickening and cognitive performance in chronic mTBI patients [31]. Popesccu et al. indicated that mTBI patients showed reduced alpha-band power in the bilateral MFG by using resting-state MEG, and the alpha-band power in the MFG was negatively correlated with scores reflecting symptoms of emotional numbing [34]. Therefore, all related studies have suggested that the PFC, specifically the MFG, might be an important part of cognitive and emotional regulation circuits; changes in this region may be associated with characteristic symptoms of cognitive impairment. Meanwhile, consistent with these valuable findings, our results are instructive for understanding the specific role of MFG abnormalities in patients with acute mTBI and suggest that MFC may provide valuable insights into the neural mechanism of acute mTBI.

In the current study, we used the GCA method to study the directed functional connection of the brain network in mTBI patients at the acute stage. The left MFG-to-whole brain GCA showed that left MFG activity predicted subsequent decreases in activity in the frontal cortex (ACC and mSFG) and temporal cortex (MTG). Previous neuroimaging studies have found that abnormalities in the frontal cortex may be the cause of cognitive impairment after mTBI. First, it has been revealed that the ACC regulates activity in the executive areas of the brain that direct attention and produce responses [35]. Changes in the ACC have been found in the MEG signals between combat-related mTBI patients and HCs by using MEG and N-back working memory tasks [36]. Furthermore, we found a negative correlation between the visuospatial/executive score and decreases in connectivity from the MFG to the ACC, which also emphasized the pivotal role of the ACC in acute mTBI. However, the exact mechanism for this correlation result is unclear. We speculated that this negative correlation may also be a compensatory effect during the first few days following mTBI drawing on the previously study [37], but this compensatory mechanism needs to be confirmed in future studies. Our current results also indicated that acute mTBI patients showed decreased causal connectivity from the left MFG to the left mSFG. This finding was in line with that of another study with rs-fMRI, which showed significantly decreased ALFFs in the SFG of mTBI patients compared with those in the SFG of HCs [38]. Popescu and colleagues’ analysis of MEG data showed that the power of the alpha band in the SFG was generally lower in mTBI patients than in HCs, and the changes in alpha-band power were negatively associated with scores reflecting symptoms of emotional numbing [34]. All these studies supported the idea that the left MFG is an important part of information processing and can coordinate working memory (e.g., short-term memory) and other sources of information that are particularly important for attention and emotional maintenance [39].

Previous fMRI studies have suggested that MTG located in the posterior temporal lobe plays a vital role in auditory and motor processing functions [40]. However, recent neuropsychological and imaging literature suggested that MTG may be important for various aspects of working memory, visual and emotional cognition perception [41]. In the present study, we also found that the mTBI group showed reduced causal connectivity from the left MFG to both sides of the MTG. One previous study provided evidence that the mTBI group had significantly higher levels of fractional anisotropy and axial diffusivity in the MTG white matter region, and the diffusion alterations were correlated with acute symptom burden in mTBI patients [42]. By using brain SPECT imaging, Bonne and colleagues found that mTBI patients in the chronic stage had reduced relative blood perfusion in the MTG [43]. All these studies suggested that the structural and functional abnormalities in the MTG may be one of the underlying mechanisms of cognitive function impairment, and given the interactions between multiple functional networks that are known to exist in the brain, this change seems reasonable. Therefore, we speculated that the MTG may be a modal semantic center that binds information from different sensory modes together. Nevertheless, the association of the MTG with mTBI has not been substantially elucidated, and further research is needed to clarify the role of the MTG in mTBI.

Additionally, the whole brain-to-left MFG GCA also revealed that acute mTBI patients had significantly increased causal connectivity from the left ACC to the left MFG, suggesting that activity in the left ACC may predict subsequent increases in activity in the left MFG. Hyper-connectivity in TBI patients has previously been reported in task-related brain function and resting-state brain function. Chen et al. found that mTBI patients showed increased activity in several areas of the same region, including the pre-exercise area and the motor cortex, assuming that the activity in these areas represented a compensation mechanism because TBI patients performed as well on memory tasks as healthy controls [37]. Sullivan et al. showed enhanced negative coupling FC between the dorsomedial PFC and the dorsal ACC in blast-related mTBI patients, and the authors postulated that the enhanced negative coupling in mTBI patients serves as a compensatory mechanism for successful task performance [13]. In a recent study of cognitive control in civilians with mTBI, the enhanced activation in the mTBI group was also interpreted to reflect a compensatory mechanism, but this activation was observed in the parietal subcortex, which is not part of the functional network discussed in the current study [44]. The use of compensatory mechanisms that substitute for cognitive resources is also thought to explain functional imaging results in studies in moderate to severe TBI patients [45]. Consistent with the above notion, our results provide further evidence that compensatory activity may allow normal levels of some cognitive function performance to be maintained in acute mTBI patients.

There are several limitations in our study. First, our experimental design is cross-sectional and limited in sample size, so it is difficult to make direct causal inferences about the relationship between brain functional network structures and cognitive impairment characteristics in patients with mTBI. Additional longitudinal studies involving more subjects are required in the future. Second, our present study is limited to patients with mTBI in different populations, who showed different injury mechanisms and different brain injury sites. Heterogeneity of the injury mechanisms may minimize the generalization of observed results to any particular injury mechanism. Distinguishing the damage models and mechanisms of mTBI and maintaining homogeneity in the study population will allow better inferences to be made for different types of injuries. Third, the meaning of causal connectivity by GCA in the static state is not completely clear, and there are still some deficiencies. It is unclear whether low-pass filtering is the best method for resting fMRI data of GCA, and further studies are needed to clarify this meaningful view. Functional magnetic resonance imaging and electrophysiology require further research to elucidate the link between causal connections and neuronal activity. Finally, cognitive impairment after mTBI is very subtle, and our MoCA cognitive assessment method may not be sufficiently sensitive to identify these differences comprehensively. Therefore, in the future, it will be worthwhile to conduct additional studies using neuropsychological assessments and more sensitive cognitive performance indicators.

Conclusions

To summarize, we have observed crucial functional network hub and causal connectivity aberrations within several regions revealed by DC and GCA in patients with mTBI at the acute stage. Compared to HCs, acute mTBI patients showed decreased FC strength in the left MFG region and abnormal directionality of influence both from and to the left MFG. Furthermore, decreased DC values in the MFG and altered causal connectivity from the left MFG to the left ACC were correlated with deficits in cognitive performance. The abnormalities in brain functional network structures are helpful in better understanding the neuropathophysiological mechanism of cognitive impairment after mTBI at the acute stage, which may help diagnose and evaluate the degree of cognitive impairment and recovery of patients to a certain extent.

Materials and Methods