Elsevier

NeuroImage

Volume 55, Issue 4, 15 April 2011, Pages 1716-1727
NeuroImage

Alteration of brain functional network at rest and in response to YMCA physical stress test in concussed athletes: RsFMRI study

https://doi.org/10.1016/j.neuroimage.2011.01.024Get rights and content

Abstract

There is still controversy in the literature whether a single episode of mild traumatic brain injury (mTBI) results in short- and/or long-term functional and structural deficits in the concussed brain. With the inability of traditional brain imaging techniques to properly assess the severity of brain damage induced by a concussive blow, there is hope that more advanced applications such as resting state functional magnetic resonance imaging (rsFMRI) will be more specific in accurately diagnosing mTBI. In this rsFMRI study, we examined 17 subjects 10 ± 2 days post-sports-related mTBI and 17 age-matched normal volunteers (NVs) to investigate the possibility that the integrity of the resting state brain network is disrupted following a single concussive blow. We hypothesized that advanced brain imaging techniques may reveal subtle alterations of functional brain connections in asymptomatic mTBI subjects. There are several findings of interest. All mTBI subjects were asymptomatic based upon clinical evaluation and neuropsychological (NP) assessments prior to the MRI session. The mTBI subjects revealed a disrupted functional network both at rest and in response to the YMCA physical stress test. Specifically, interhemispheric connectivity was significantly reduced in the primary visual cortex, hippocampal and dorsolateral prefrontal cortex networks (p < 0.05). The YMCA physical stress induced nonspecific and similar changes in brain network connectivity patterns in both the mTBI and NV groups. These major findings are discussed in relation to underlying mechanisms, clinical assessment of mTBI, and current debate regarding functional brain connectivity in a clinical population. Overall, our major findings clearly indicate that functional brain alterations in the acute phase of injury are overlooked when conventional clinical and neuropsychological examinations are used.

Graphical Abstract

Functional connectivity diagrams for normal volunteers (A) and mTBI (B) subjects indicating reduction of hippocampal interhemispheric correlations in mTBI subjects as reflected in the thickness of the red line between the right and left hippocampi.

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Research Highlights

►mTBI subjects were asymptomatic based on clinical evaluation prior to MRI. ►mTBI subjects revealed a disrupted brain functional networks. ►The YMCA stress rest induced non-specific changes in brain network.

Introduction

Over the last two decades, it has been challenging to establish clear links between the observable neuropsychological and behavioral symptoms of mild traumatic brain injury (mTBI) and the underlying structural/functional deficits using clinically available brain imaging techniques (see Schrader et al., 2009 for review). However, advances in brain imaging methodologies have revealed important information regarding both structural (Bazarain et al., 2007; Wozniak et al., 2007; Wilde et al., 2008) and functional (McAllister et al., 2001, McAllister et al., 2006, Slobounov et al., 2010) alteration in subjects suffering from mTBI. It should be noted that “traditional” analysis of the brain correlating with behavior is mostly implemented by focusing on alteration of the brain signal from local regions of interests (ROIs). For example there is evidence that suggests a variety of functional deficits in concussed individuals that correlate with brain imaging (functional magnetic resonance imaging: fMRI) data (Ptito et al., 2007). McAllister et al. (2001) have shown enhanced and diffuse activation primarily in the prefrontal cortex (PFC) of concussed subjects who have successfully performed the required cognitive tasks. Similarly, Jantzen et al. (2004) observed increased activation in the parietal frontal and cerebellar regions in concussed individuals when compared with pre-injury fMRI data although there were no changes in the subjects' cognitive performance. In our recent fMRI study, we observed larger cortical networks and additional increases in activity outside common ROIs in mTBI subjects when compared to normal volunteers (NVs), during spatial navigation working memory tasks (Slobounov et al., 2010). Both mTBI and NVs displayed nearly identical performance and success rates for each task. In contrast, Chen et al. (2004) reported the opposite fMRI findings suggesting a reduced blood oxygen level dependent (BOLD) signal in the mid-dorsolateral prefrontal cortex (DL-PFC) in symptomatic concussed athletes, who also performed poorly on the working memory tasks. Although the nature of these discrepancies is beyond the scope of this report, it should be noted that one of the possible reasons is variation in subjects' inclusion criteria and performance level.

Clearly the human brain has two contradictory properties: (1) “segregation”, which means localization of specific functions; and (2) “integration”, which means combining all the information and functions at a global level within the conceptual framework of a “global integrated network” (Varela et al., 2001, Reijneveld et al., 2007). Consistent with this conceptual framework, Biswal et al. (1995) were the first to document the spontaneous fluctuations within the somatosensory system and high potential for functional connectivity in resting state functional MRI (rsFMRI) using intrinsic activity correlations. Since this discovery of coherent spontaneous fluctuations, a many studies have shown that several brain regions engaged during various cognitive tasks also form coherent large-scale brain networks that can be identified using rsFMRI (Smith et al., 2009). More recently, neurophysiological correlates underlying rsFMRI were documented specifically emphasizing the links between rsFMRI connectivity and inter-areal synchronization observed with intracranial EEG (see Jerbi et al., 2010 for review).

The existence of a “default network” in the brain during the resting state was reported by Greicius et al. (2003). Both functional and structural connectivity between brain regions were examined to detect whether there are orderly sets of regions that have particularly high local connections (forming families of clusters) as well as a limited number of regions that serve as relay stations or hubs (Sporns et al., 2007). It was suggested that the neural network of the brain has a small-world structure, namely, high-cluster coefficients and low average path length allowing optimization of information processing (Reijneveld et al., 2007). Overall, network analysis is necessary to explore the integration phenomena observed in both resting states and in response to high-level information processing in the brain induced by cognitive and/or motor tasks.

Recent advances in brain imaging technologies offer tremendous promise for improving clinical applicability of fMRI with specific focus on spontaneous modulations in the BOLD signal that occur during resting state conditions (see Fox and Raichle, 2007 for review). In contrast to the traditional task-related approach, resting state studies observe the brain in the absence of overt task performance and/or stimulation. In this approach, subjects are generally asked to lie quietly with eyes closed or while fixating on a crosshair. In fact, no consensus exists as to whether there is a significant impact of the precise experimental setting (e.g., with eyes open, eyes closed, or fixation) on the stability of correlation matrix (see Cole et al., 2010, for details). Spontaneous modulation in the BOLD signal in the absence of any explicit input or output is then recorded and analyzed. One of the reasons to use resting state functional connectivity (fcFMRI) for clinical applications is that the task-related increases in neuronal metabolism are usually small (< 5%) when compared to the large resting energy consumption (20% of the body's energy, most of which supports ongoing neuronal signaling) (Raichle and Mintun, 2006). Overall, ongoing spontaneous activity provides a window into the neural processing that appears to consume the vast majority of the brain resources, which might provide a more accurate and richer source of disease-related BOLD signal change (Fox and Greicius, 2010).

Functional abnormalities of the brain are associated with pathological changes in connectivity and network structures. There are varying methodologies [e.g., graph analysis, Granger causality, independent component analysis (ICA), seed-based correlation, and more recently, extended unified structural equation modeling (SEM) approach, Gates et al., 2011] to examine spontaneous BOLD oscillations which reflect enduring and intrinsic properties of the brain and can allow us to obtain a more general characterization of brain dysfunction in psychiatric populations, including ADHD, autism, depression, PTSD, and schizophrenia (see Fornito et al., 2010; Fox and Greicius, 2010 for review). A few recent fMRI reports also indicated a predominant loss of long-distance functional connections in the resting state in patients suffering from Alzheimer's disease (AD) (Zhou et al., 2008; Rosenbaum et al., 2008). Departures from a “small world” network (Watts and Strogatz, 1998) configuration in neurological populations including stroke, tumors, multiple sclerosis, epilepsy have been reported, and have also brought new insight into better understanding the pathophysiology of these diseases affecting specific local and/or global brain networks (see Guye et al., 2010 for review). More recently Nakamura et al. (2009), using the graph theory, examined neural network properties at separate time points during recovery from severe traumatic brain injury. They reported that the strength but not the number of network connections diminished during the acute phase of TBI indicating disruption of the neural system. Marquez de la Plata et al. (in press) also reported a deficit in the functional connectivity of the hippocampus and frontal lobe circuits six months after traumatic diffuse axonal injury (DAI).

The majority of approaches to analyze rsFMRI data have been driven using spatial models with a strong a priori hypothesis regarding the functional connectivity of a small number of brain ROIs or individual voxel locations of interest (Cole et al., 2010). With regard to traumatic brain injury (TBI), hippocampal and DL-PFC networks were recently identified and studied (Marquez de la Plata et al., in press). Few other TBI-related fMRI studies have focused on these ROIs due to their functional alteration, in isolation or in conjunction with other brain regions (McAllister et al., 2001, Chen et al., 2003, Nakamura et al., 2009, Slobounov et al., 2010). In the present study, we utilized an a priori hypothesis approach focusing on alterations of several interhemispheric brain functional networks at rest and in response to the YMCA physical stress test in subjects suffering from sports-related mTBI. We hypothesized that interhemispheric connectivity within hippocampal, visual, DL-PFC and precuneus networks may be altered in mTBI subjects with a more pronounced effect induced by the physical stress test.

Section snippets

Participants

Seventeen neurologically normal student-athletes with no history of mTBI (mean age 21.3 ± 1.5 years) and 17 student-athletes (mean age 20.8 ± 1.7 years) who had recently suffered a sports-related mTBI (collegiate rugby, ice hockey and soccer players) were recruited for this study. The sample was 65% male and 35% female. Academic grade average score for all subjects under study was 3.2 ± 0.5. All injured subjects suffered from grade 1 mTBI (Cantu Data Driven Revised Concussion Grading Guideline, 2006)

Neuropsychological (NP) test performance data

Table 1 shows the neuropsychological data for the concussion (mTBI) and normal volunteers (NV) groups. As can be seen from the data presented in Table 1, there were no significant differences between mTBI subjects and NVs for all the variables under NP testing (p > 0.05).

Heart rate dynamics data

As noted before (see Methods section), the subjects' heart rates were constantly monitored to accommodate the requirements for the YMCA bike protocol as well as to control for the rate of recovery while subjects were in the

Discussion

It is important to better delineate alterations in the brain's functional network possibly linked to both short- and long-term subtle cognitive and/or behavioral impairment in mild TBI. Indeed, there is a growing evidence to support the notion that “asymptomatic” mTBI subjects may have residual brain abnormalities, which may be assessed by advanced brain imaging techniques, putting these individual at high risk for recurrent brain injuries (Slobounov et al., 2009, 2010). The resting state

Acknowledgments

This study was supported by NIH Grant RO1 NS056227-01A2 “Identification of Athletes at Risk for Traumatic Brain Injury” awarded to Dr. Slobounov, PI.

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